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RFC_IV_Split

Description: Chemotherapy Protocol CHRONIC LYMPHOCYTIC LEUKAEMIA CYCLOPHOSPHAMIDE-FLUDARABINE-RITUXIMAB (IV-Split) Regimen • CLL – RFC (IV)-Cyclophosphamide-Fludarabine-Rituximab (IV-Split) Indication • Chronic Lymphocytic Leukaemia • The rituximab split dose is indicated where the lymphocytes are greater than 25x109/L Toxicity Drug Cyclophosphamide Fludarabine Rituximab Adverse Effect Dysuria, haemorrhagic cystitis (rare), taste disturbances Transfusion related GVHD, neurotoxicity, opportunistic infections, GI disturbances Severe cytokine release syndrome, increased incidence of infective complications, progressive multifocal leukoencephalopathy Patients treated with fludarabine carry a lifelong risk of transfusion associated graft versus host disease (TA-GVHD). Where blood products are required these patients must receive only irradiated blood products for life. Local blood transfusion departments must be notified as soon as the decision to treat is made and the patient must be issued with an alert card to carry with them at all times. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Drugs • FBC, LFTs and U&Es prior to day one of treatment • Hepatitis B status prior to starting treatment with rituximab Dose Modifications The dose modifications listed are for haematological, liver and renal function and some drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. In principle all dose reductions due to adverse drug reactions should not be re-escalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Version 1 (February 2017) Page 1 of 10 CLL- RFC (IV)-Cyclophosphamide-Fludarabine-Rituximab (IV-Split) Haematological Dose modifications for haematological toxicity in the table below are for general guidance only. Always refer to the responsible consultant as any dose reductions or delays will be dependent on clinical circumstances and treatment intent. Low counts can be a consequence of bone marrow infiltration as well as drug toxicity. Consider blood transfusion or erythropoietin if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL. Irradiated blood products must be used (fludarabine). Dose modifications based on haematological parameters apply to cyclophosphamide and fludarabine only. Rituximab rarely has to be dose adjusted for haematological toxicity. Neutrophils (x109/L) more than 1 0.5-1 Platelets (x109/L) more than 75 50-75 Dose Modifications (cyclophosphamide and fludarabine) 100% Delay for 7 days and if counts recover give 100% doses. If 14 days are required for counts to recover then re-start with a 50% dose reduction Dose Modifications 100% Delay for 7 days and if counts recover give 100% doses. If 14 days are required for counts to recover then re-start with a 50% dose reduction Hepatic Impairment Please note that the approach may be different where abnormal liver function tests are due to disease involvement. Drug Cyclophosphamide Bilirubin (µmol/L) more than 21 or AST/ALT (units) 2-3xULN Dose (%of original dose) Clinical decision. Evidence that exposure to active metabolites may not be increased, suggesting dose reduction may not be necessary Fludarabine N/A N/A No dose adjustment required Rituximab N/A N/A No dose adjustment needed Version 1 (February 2017) Page 2 of 10 CLL- RFC (IV)-Cyclophosphamide-Fludarabine-Rituximab (IV-Split) Renal Impairment Drug Cyclophosphamide Fludarabine Creatinine Clearance (ml/min) more than 20 10-20 less than 10 greater than 70 30-70 less than 30 Dose (% of original dose) 100% 75% omit 100% 50% omit Rituximab N/A No dose adjustment needed Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. In general for all other non-haematological NCI-CTC grade 3 and above toxicities delay treatment until the adverse effect has resolved to NCI-CTC grade 2 or below. The dose should then be reduced to 75% of the original dose. If toxicity recurs delay until recovery and further dose reduce to 50% of the original dose or discontinue as appropriate. Rituximab Infusion related adverse reactions have been observed in 10% of patients treated with rituximab. Rituximab administration is associated with the onset of cytokine release syndrome. This condition is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. It may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, acute renal failure, elevated lactate dehydrogenase (LDH) and can lead to acute respiratory failure and death. This effect on the lungs may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. Cytokine release syndrome frequently occurs within one or two hours of initiating the first infusion. Hypersensitivity reactions, including anaphylaxis, have been reported following the intravenous administration of proteins. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes of starting the infusion. Medicinal products for the treatment of allergic reactions should be available for immediate use in the event of hypersensitivity developing during the administration of rituximab. Use of rituximab may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening neurological, cognitive or psychiatric symptoms that may be suggestive of PML. If Version 1 (February 2017) Page 3 of 10 CLL- RFC (IV)-Cyclophosphamide-Fludarabine-Rituximab (IV-Split) PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed the rituximab must be permanently discontinued. Regimen 28 day cycle for 6 cycles Cycle 1 Drug Cyclophosphamide Fludarabine Dose 250mg/m2 25mg/m2 Rituximab 100mg Rituximab 325mg/m2 Days 1, 2, 3 1, 2, 3 1 2 Administration Intravenous bolus Intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Intravenous infusion in 50ml sodium chloride 0.9% over 120 minutes Intravenous infusion in 500ml sodium chloride 0.9% starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour Cycle 2 onwards Drug Dose Cyclophosphamide 250mg/m2 Fludarabine 25mg/m2 Rituximab 500mg/m2 Days 1, 2, 3 1, 2, 3 1 Administration Intravenous bolus Intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Intravenous infusion in 500ml sodium chloride 0.9% as per local rituximab infusion guidelines* *If the lymphocyte is greater than 25x109/L on day one then consider fractionating the dose of rituximab as follows; Day 1 - rituximab 125mg/m2 in 100ml sodium chloride 0.9% Day 2 - rituximab 375mg/m2 in 500ml sodium chloride 0.9% If there were no problems with the previous infusion then start both fractions at 100mg/hour and escalate the rate in 100mg/hour increments every 30 minutes to a maximum rate of 400mg/hour. If reactions occurred with the previous cycle, give both fractions starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour Dose Information • Cyclophosphamide will be dose banded according to the agreed local bands (up if halfway) • Fludarabine will be dose banded according to the national dose bands (up if halfway) Version 1 (February 2017) Page 4 of 10 CLL- RFC (IV)-Cyclophosphamide-Fludarabine-Rituximab (IV-Split) • The dose of rituximab from 325mg/m2 and above will be dose rounded to the nearest 100mg (up if halfway) Administration Information Extravasation • Cyclophosphamide – non-vesicant • Fludarabine – non-vesicant • Rituximab - neutral Other • The rate of administration of rituximab varies. The cycle two administration of rituximab should be given using the licensed administration schedule. Thereafter, refer to the local rituximab administration guidelines. Additional Therapy • Antiemetics As take home medication - metoclopramide 10mg three times a day when required oral - ondansetron 8mg twice a day on days of chemotherapy administration • Rituximab pre-medication 30 minutes prior to rituximab - chlorphenamine 10mg intravenous - hydrocortisone 100mg intravenous - paracetamol 1000mg oral • Rituximab infusion reactions - hydrocortisone 100mg intravenous when required for rituximab infusion related reactions - salbutamol 2.5mg nebule when required for rituximab related bronchospasm - consider pethidine 25-50mg intravenous bolus for rituximab related rigors that fail to respond to steroids. • Allopurinol 300mg once a day oral for 7 days of the first cycle only oral • Anti-infective prophylaxis with; - aciclovir 400mg twice a day oral - co-trimoxazole 960mg once a day on Monday, Wednesday and Friday only oral • Mouthwashes according to local or national policy on the treatment of mucositis. Version 1 (February 2017) Page 5 of 10 CLL- RFC (IV)-Cyclophosphamide-Fludarabine-Rituximab (IV-Split) • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleeding. Coding • Procurement – X71.5 • Delivery – X72.1, X72.2, X72.4 References 1.Keating M et al. Early Results of a Chemoimmunotherapy Regimen of Fludarabine, Cyclophosphamide, and Rituximab as initial therapy for chronic lymphocytic leukaemia. J Clin Oncol (2005); 23 (18): 4079-4088 2. Tam CS et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukaemia. Blood (2008); 112:975-980 3. Wierda W et al. Chemoimmunotherapy with Fludarabine, Cyclophosphamide, and Rituximab for Relapsed and Refractory Chronic Lymphocytic Leukaemia. J Clin Oncol (2005); 23:4070-4078 Version 1 (February 2017) Page 6 of 10 CLL- RFC (IV)-Cyclophosphamide-Fludarabine-Rituximab (IV-Split) REGIMEN SUMMARY RFC-Cyclophosphamide-Fludarabine-Rituximab (IV-Split) Cycle 1 Day One 1 Warning – Check blood transfusion status Administration Instructions Patients treated with fludarabine carry a lifelong risk of transfusion associated graft versus host disease. Where blood products are required these patients must receive ONLY IRRADIATED BLOOD PRODUCTS for life. Ensure transfusion departments are notified and the patient has been issued with an alert card 2. Chlorphenamine 10mg intravenous 3. Hydrocortisone 100mg intravenous 4. Paracetamol 1000mg oral 5. Rituximab 100mg intravenous infusion in 50ml sodium chloride 0.9% over 120 minutes 6. Ondansetron 8mg oral or intravenous 7. Cyclophosphamide 250mg/m2 intravenous bolus 8. Fludarabine 25mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes 9. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 10. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Day Two 11. Chlorphenamine 10mg intravenous 12. Hydrocortisone 100mg intravenous 13. Paracetamol 1000mg oral 14. Rituximab 325mg/m2 intravenous infusion in 500ml sodium chloride 0.9% Administration Guidelines Start at a rate of 50mg/hour and, if tolerated, increase by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour. 15. Warning – Check ondansetron Administration Instructions Please check that the patient has taken ondansetron on the morning of treatment. If they have not administer ondansetron 8mg oral or intravenous Version 1 (February 2017) Page 7 of 10 CLL- RFC (IV)-Cyclophosphamide-Fludarabine-Rituximab (IV-Split) 16. Cyclophosphamide 250mg/m2 intravenous bolus 17. Fludarabine 25mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes 18. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 19. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Day Three 20. Warning – Check ondansetron Administration Instructions Please check that the patient has taken ondansetron on the morning of treatment. If they have not administer ondansetron 8mg oral or intravenous 21. Cyclophosphamide 250mg/m2 intravenous bolus 22. Fludarabine 25mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Take home medicines (day one only) 23. Allopurinol 300mg once a day for 7 days oral 24. Metoclopramide 10mg three times a day when required oral Administration Instructions Supply an original pack of 28 tablets or nearest equivalent 25. Ondansetron 8mg twice a day for 5 days oral starting on the evening of day one of the chemotherapy cycle 26. Aciclovir 400mg twice a day for 28 days oral 27. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday for 28 days oral Cycle 2 onwards Day One 28. Chlorphenamine 10mg intravenous 29. Hydrocortisone 100mg intravenous 30. Paracetamol 1000mg oral 31. Rituximab 500mg/m2 intravenous infusion in 500ml sodium chloride 0.9% as per the rituximab administration guidelines Administration Instructions Administer as per your local administration guidelines If the lymphocyte is greater than 25x109/L on day one then consider fractionating the dose of rituximab as follows; Version 1 (February 2017) Page 8 of 10 CLL- RFC (IV)-Cyclophosphamide-Fludarabine-Rituximab (IV-Split) Day 1 - rituximab 125mg/m2 in 100ml sodium chloride 0.9% Day 2 - rituximab 375mg/m2 in 500ml sodium chloride 0.9% If there were no problems with the previous infusion then start both fractions at 100mg/hour and escalate the rate in 100mg/hour increments every 30 minutes to a maximum rate of 400mg/hour. If reactions occurred with the previous cycle, give both fractions starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour 32. Ondansetron 8mg oral or intravenous 33. Cyclophosphamide 250mg/m2 intravenous bolus 34. Fludarabine 25mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes 35. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 36. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Day Two and Three 37. Warning – Check ondansetron Administration Instructions Please check that the patient has taken the ondansetron on the morning of treatment. If they have not administer ondansetron 8mg oral or intravenous 38. Cyclophosphamide 250mg/m2 intravenous bolus 39. Fludarabine 25mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Take home medicines (day one only) 40. Metoclopramide 10mg three times a day when required oral Administration Instructions Supply an original pack of 28 tablets or nearest equivalent 41. Ondansetron 8mg twice a day for 5 days oral starting on the evening of day one of the chemotherapy cycle 42. Aciclovir 400mg twice a day for 28 days oral 43. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday for 28 days oral Version 1 (February 2017) Page 9 of 10 CLL- RFC (IV)-Cyclophosphamide-Fludarabine-Rituximab (IV-Split) DOCUMENT CONTROL Version Date Amendment Written By Approved By 1 February 2017 None Dr Deborah Wright Pharmacist Dr Helen Dignum Consultant Haematologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. Version 1 (February 2017) Page 10 of 10 CLL- RFC (IV)-Cyclophosphamide-Fludarabine-Rituximab (IV-Split)
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IdelalisibRituximab

Description: Chemotherapy Protocol Chronic Lymphocytic Leukaemia (CLL) Idelalisib-Rituximab Regimen • CLL – Idelalisib-Rituximab Indication • Chronic lymphocytic leukaemia in adults when the disease has been treated but has relapsed within 24 month • Disease modification Toxicity Drug Idelalisib Rituximab Adverse Effect Diarrhoea, colitis, pneumonitis, rash Severe cytokine release syndrome, increased incidence of infective complications, progressive multifocal leukoencephalopathy The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring • FBC, U&Es and LFTs on day one of the cycle and at least every 14 days for the first 6 months of treatment (every 7 days when the neutrophil count is less than 1x109/l). • CMV PCR in blood (EDTA) should be monitored every 4 weeks throughout treatment. Idelalisib should be discontinued during confirmed CMV viraemia (PCR positivity in more than two consecutive samples taken one week apart). • Hepatitis B status prior to starting treatment with rituximab Dose Modifications The dose modifications listed are for haematological, liver and renal function and drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Haematological Dose modifications for haematological toxicity in the table below are for general guidance only. Always refer to the responsible consultant as any dose reductions or delays will be dependent on clinical circumstances and treatment intent. Consider blood transfusion or the use of erythropoietin according to NICE TA323 if the patient is symptomatic of anaemia or where the haemoglobin is less than 8g/dL (80g/L) Version 1 (February 2017) Page 1 of 11 CLL-Idelalisib-Rituximab If the neutrophil count is 1x109/L or above continue with idelalisib at the recommended dose. If the neutrophils are between 0.5-1x109/L maintain the idelalisib dosing and monitor the neutrophil count weekly. If the count drops below 0.5x109/L then interrupt the idelalisib dosing and monitor the counts weekly. Once the counts recover re-start treatment at 100mg twice a day The dose of rituximab is rarely adjusted for haematological parameters. Hepatic Impairment Patients with hepatic impairment should be closely monitored for signs and symptoms of toxicity. If the ALT rises to between 3-5xULN, then monitor the liver function more regularly. Idelalisib should be discontinued if the ALT is greater than 5xULN, until it falls to less than 3xULN. The idelalisib can then restart at 100mg twice a day, considering an increase back up to 150mg twice a day if the liver function remains stable. If the ALT rises again to more than 5xULN, withhold idelalisib until it is less than 3xULN and consider restarting at 100mg twice a day at the discretion of the consultant. Rituximab does not require dose adjustment in hepatic impairment. Renal Impairment Dose adjustment is not considered necessary in renal impaired patients. Patients with evidence of impaired renal function should be carefully monitored as they are prone to additional myelosuppression. Rituximab does not require dose adjustment in renal impairment. Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. In general for all other non-haematological NCI-CTC grade 3 and above toxicities delay treatment until the adverse effect has resolved to NCI-CTC grade 2 or below. The dose should then be reduced to 75% of the original dose. If toxicity recurs delay until recovery and further dose reduce to 50% of the original dose or discontinue as appropriate. Idelalisib Diarrhoea Idelalisib must be withheld in the event of an NCI-CTC grade 3 or above diarrhoea. It may be restarted once the diarrhoea has resolved to grade 1 or less at 100mg twice a day. If the symptom does not re-occur then the dose may be incremented back to 150mg twice a day. Version 1 (February 2017) Page 2 of 11 CLL-Idelalisib-Rituximab Pneumonitis Idelalisib must be withheld in the event of suspected pneumonitis and the patient treated accordingly. Once the pneumonitis has resolved and re-treatment is considered appropriate, resume at 100mg twice a day. Rash Withhold idelalisib in the event of a NCI-CTC grade 3 or above rash. Once the rash has resolved to grade 1 or less, restart the idelalisib at 100mg twice a day. Consider reescalation to 150mg twice a day if the rash does not recur. Rituximab Infusion Related Reactions Infusion related adverse reactions have been observed in 10% of patients treated with rituximab. Rituximab administration is associated with the onset of cytokine release syndrome. This condition is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. It may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, acute renal failure, elevated lactate dehydrogenase (LDH) and can lead to acute respiratory failure and death. This effect on the lungs may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. Cytokine release syndrome frequently occurs within one or two hours of initiating the first infusion. Hypersensitivity reactions, including anaphylaxis, have been reported following the intravenous administration of proteins. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes of starting the infusion. Medicinal products for the treatment of allergic reactions should be available for immediate use in the event of hypersensitivity developing during the administration of rituximab. Progressive Multifocal Leukoencephalopathy Use of rituximab may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening neurological, cognitive or psychiatric symptoms that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed the rituximab must be permanently discontinued. Version 1 (February 2017) Page 3 of 11 CLL-Idelalisib-Rituximab Regimen 28 day cycle for 6 cycles Cycle 1 Drug Idelalisib Rituximab Rituximab Rituximab Dose 150mg twice a day 100mg 325mg/m2 500mg/m2 Days 1-28 inclusive 1 2 14 Administration Oral Intravenous infusion in 50ml sodium chloride 0.9% over 120 minutes Intravenous infusion in 500ml sodium chloride 0.9% starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour Intravenous infusion in 500ml sodium chloride 0.9% as per your local rituximab administration guidelines* Cycle 2 Drug Idelalisib Rituximab Dose 150mg twice a day 500mg/m2 Days 1-28 inclusive 1, 14 Administration Oral Intravenous infusion in 500ml sodium chloride 0.9% as per your local rituximab administration guidelines* Cycle 3, 4, 5, 6 Drug Idelalisib Rituximab Dose 150mg twice a day 500mg/m2 Days 1-28 incl. 1 Administration Oral Intravenous infusion in 500ml sodium chloride 0.9% as per your local rituximab administration guidelines* *If the lymphocyte is greater than 25x109/L on day one then consider fractionating the dose of rituximab as follows; Day 1 - rituximab 125mg/m2 in 100ml sodium chloride 0.9% Day 2 - rituximab 375mg/m2 in 500ml sodium chloride 0.9% If there were no problems with the previous infusion then start both fractions at 100mg/hour and escalate the rate in 100mg/hour increments every 30 minutes to a maximum rate of 400mg/hour. If reactions occurred with the previous cycle, give both fractions starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour Version 1 (February 2017) Page 4 of 11 CLL-Idelalisib-Rituximab Dose Information • Idelalisib is available as 100mg and 150mg film-coated tablets. • The dose of rituximab for the 50mg/m2 - 125mg/m2 dose will be rounded as per the national dose bands (10mg/ml) • The dose of rituximab from 325mg/m2 and above will be dose rounded to the nearest 100mg (up if halfway) Administration Information • Idelalisib should be swallowed whole, either with or without food. • If the patient misses a dose of idelalisib within 6 hours of the time it is usually taken, the patient should take the missed dose as soon as possible and resume the normal dosing schedule. If a patient misses a dose by more than 6 hours, the patient should not take the missed dose and simply resume the usual dosing schedule. • The rate of administration of rituximab varies. Please refer to the rituximab administration guidelines. Additional Therapy • No routine anti-emetics are required. They may be added from “favourites” on ARIA for individual patients who may require treatment for nausea and vomiting. • Rituximab pre-medication 30 minutes prior to rituximab - chlorphenamine 10mg intravenous - hydrocortisone 100mg intravenous - paracetamol 1000mg oral • Rituximab infusion reactions - hydrocortisone 100mg intravenous when required for rituximab infusion related reactions - salbutamol 2.5mg nebule when required for rituximab related bronchospasm - consider pethidine 25mg intravenous bolus for rituximab related rigors that fail to respond to corticosteroids. This should follow a verbal confirmation from a doctor that the dose is to be administered. • Anti-infective prophylaxis as follows - aciclovir 400mg twice a day oral - co-trimoxazole 960mg once a day on Monday, Wednesday and Friday only oral (this should be continued for up to six months after treatment has finished) • Patients with CLL are at risk of tumour lysis syndrome (TLS). The British Society of Haematology guidelines are a useful reference source. Oral allopurinol is one option for prophylaxis (300mg once a day oral for 7 days in he first cycle will be set in Version 1 (February 2017) Page 5 of 11 CLL-Idelalisib-Rituximab ARIA). Intravenous rasburicase can be considered in high risk individuals. • Loperamide 4mg after the first loose stool and 2mg after each loose motion thereafter to a maximum of 16mg / 24 hours when required for the relief of diarrhoea • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. Additional Information • The National Patient Safety Alert on oral chemotherapy (NPSA/2008/RRR001) must be followed in relation to idelalisib. • It must be made clear to all staff, including those in the community, that idelalisib should only be prescribed under the supervision of a consultant haematologist. • Idelalisib is associated with many drug interactions. Coding • Procurement – X • Delivery – X References 1. Furman R et al. Idelalisib in relapsed chronic lymphocytic leukemia. N Engl J Med (2014): 370: 997-1007 Version 1 (February 2017) Page 6 of 11 CLL-Idelalisib-Rituximab REGIMEN SUMMARY Cycle 1 Idelalisib-Rituximab Day 1 1. Chlorphenamine 10mg intravenous 2. Hydrocortisone 100mg intravenous 3. Paracetamol 1000mg oral 4. Rituximab 100mg intravenous infusion in 50ml sodium chloride 0.9% over 120 minutes 5. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 6. Pethidine 25mg intravenous bolus in 10ml sodium chloride 0.9% over 5 minutes for the relief of rigors Administration Instructions For the relief of rigors following a verbal confirmation from a doctor that the dose is to be given. 7. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Day 2 8. Chlorphenamine 10mg intravenous 9. Hydrocortisone 100mg intravenous 10. Paracetamol 1000mg oral 11. Rituximab 325mg/m2 intravenous infusion in 500ml sodium chloride 0.9% Administration Instructions Administer at a rate of 50mg/hour increasing by 50mg/hour every 30 minutes if tolerated to a maximum rate of 400mg/hour. 12. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 13. Pethidine 25mg intravenous bolus in 10ml sodium chloride 0.9% over 5 minutes for the relief of rigors Administration Instructions For the relief of rigors following a verbal confirmation from a doctor that the dose is to be given. 14. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Day 14 15. Chlorphenamine 10mg intravenous 16. Hydrocortisone 100mg intravenous Version 1 (February 2017) Page 7 of 11 CLL-Idelalisib-Rituximab 17. Paracetamol 1000mg oral 18. Rituximab 500mg/m2 intravenous infusion in 500ml sodium chloride 0.9% Administration Instructions Administer as per your local administration guidelines If the lymphocyte is greater than 25x109/L on day one then consider fractionating the dose of rituximab as follows; Day 1 - rituximab 125mg/m2 in 100ml sodium chloride 0.9% Day 2 - rituximab 375mg/m2 in 500ml sodium chloride 0.9% If there were no problems with the previous infusion then start both fractions at 100mg/hour and escalate the rate in 100mg/hour increments every 30 minutes to a maximum rate of 400mg/hour. If reactions occurred with the previous cycle, give both fractions starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour 19. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 20. Pethidine 25mg intravenous bolus in 10ml sodium chloride 0.9% over 5 minutes for the relief of rigors Administration Instructions For the relief of rigors following a verbal confirmation from a doctor that the dose is to be given. 21. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Take Home Medicines (day one only) 22. Idelalisib 150mg twice a day for 28 days oral Administration Information Oral chemotherapy. Idelalisib should be swallowed whole, either with or without food. 23. Allopurinol 300mg once a day for 7 days oral 24. Aciclovir 400mg twice a day for 28 days oral 25. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday for 28 days oral Administration Instructions This may be taken as 480mg twice a day on Monday, Wednesday and Friday only 26. Loperamide 4mg after the first loose stool then 2mg after each loose motion thereafter to a maximum of 16mg/24 hours Administration Instructions Please supply an original pack (28 capsules or nearest equivalent) Cycle 2 Day 1, 14 27. Chlorphenamine 10mg intravenous 28. Hydrocortisone 100mg intravenous 29. Paracetamol 1000mg oral Version 1 (February 2017) Page 8 of 11 CLL-Idelalisib-Rituximab 30. Rituximab 500mg/m2 intravenous infusion in 500ml sodium chloride 0.9% Administration Instructions Administer as per your local administration guidelines If the lymphocyte is greater than 25x109/L on day one then consider fractionating the dose of rituximab as follows; Day 1 - rituximab 125mg/m2 in 100ml sodium chloride 0.9% Day 2 - rituximab 375mg/m2 in 500ml sodium chloride 0.9% If there were no problems with the previous infusion then start both fractions at 100mg/hour and escalate the rate in 100mg/hour increments every 30 minutes to a maximum rate of 400mg/hour. If reactions occurred with the previous cycle, give both fractions starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour 31. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 32. Pethidine 25mg intravenous bolus in 10ml sodium chloride 0.9% over 5 minutes for the relief of rigors Administration Instructions For the relief of rigors following a verbal confirmation from a doctor that the dose is to be given. 33. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Take Home Medicines (day one only) 34. Idelalisib 150mg twice a day for 28 days oral Administration Information Oral chemotherapy. Idelalisib should be swallowed whole, either with or without food. 35. Aciclovir 400mg twice a day for 28 days oral 36. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday for 28 days oral Administration Instructions This may be taken as 480mg twice a day on Monday, Wednesday and Friday only Cycles 3, 4, 5, 6 Day 1 37. Chlorphenamine 10mg intravenous 37. Hydrocortisone 100mg intravenous 38. Paracetamol 1000mg oral 39. Rituximab 500mg/m2 intravenous infusion in 500ml sodium chloride 0.9% Administration Instructions Administer as per your local administration guidelines If the lymphocyte is greater than 25x109/L on day one then consider fractionating the dose of rituximab as follows; Day 1 - rituximab 125mg/m2 in 100ml sodium chloride 0.9% Day 2 - rituximab 375mg/m2 in 500ml sodium chloride 0.9% If there were no problems with the previous infusion then start both fractions at 100mg/hour and escalate the rate in 100mg/hour increments every 30 minutes to a maximum rate of 400mg/hour. If reactions occurred with the previous cycle, give both fractions starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour Version 1 (February 2017) Page 9 of 11 CLL-Idelalisib-Rituximab 40. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 41. Pethidine 25mg intravenous bolus in 10ml sodium chloride 0.9% over 5 minutes for the relief of rigors Administration Instructions For the relief of rigors following a verbal confirmation from a doctor that the dose is to be given. 42. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Take Home Medicines (day one only) 43. Idelalisib 150mg twice a day for 28 days oral Administration Information Oral chemotherapy. Idelalisib should be swallowed whole, either with or without food. 44. Aciclovir 400mg twice a day for 28 days oral 45. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday for 28 days oral Administration Instructions This may be taken as 480mg twice a day on Monday, Wednesday and Friday only Version 1 (February 2017) Page 10 of 11 CLL-Idelalisib-Rituximab DOCUMENT CONTROL Version Date Amendment Written By Approved By 1 February 2017 None Dr Deborah Wright Pharmacist Dr Helen Dignam Consultant Hamematologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. Version 1 (February 2017) Page 11 of 11 CLL-Idelalisib-Rituximab
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/CLL/IdelalisibRituximab.pdf

Chlorambucil_7_Rituximab_Split

Description: Chemotherapy Protocol Chronic Lymphocytic Leukaemia (CLL) Chlorambucil (7 day)-Rituximab (Split) Regimen • CLL – Chlorambucil (7 day)-Rituximab (Split) Indication • Treatment of CLL in elderly patients for whom treatment with fludarabine and cyclophosphamide or chlorambucil and obinutuzumab or bendamustine is not considered appropriate, due to co-morbidities or performance status • Split dose rituximab is indicated where the lymphocyte count is greater than 25x109/L • Disease modification Toxicity Drug Chlorambucil Rituximab Adverse Effect Neutropenia, thrombocytopenia, anaemia, nausea, vomiting, diarrhoea, mouth ulceration, rash Severe cytokine release syndrome, increased incidence of infective complications, progressive multifocal leukoencephalopathy The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring • FBC, U&Es and LFTs on day one of the cycle • Hepatitis B status prior to starting treatment with rituximab Dose Modifications The dose modifications listed are for haematological, liver and renal function and drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Haematological Dose modifications for haematological toxicity in the table below are for general guidance only. Always refer to the responsible consultant as any dose reductions or delays will be dependent on clinical circumstances and treatment intent. Consider blood transfusion or the use of erythropoietin according to NICE TA323 if the patient is symptomatic of anaemia or where the haemoglobin is less than 8g/dL. Version 1 (February 2017) Page 1 of 8 CLL-Chlorambucil (7 day)-Rituximab (Split) The dose of rituximab is rarely adjusted for haematological parameters. Neutrophils (x109/L) more than 1 0.5 - 1 less than 0.5 and / or Platelets (x109/L) more than 75 and / or 50 - 75 and / or less than 50 Chlorambucil Dose 100% Delay treatment for one week. If counts recover treatment can be re-started. If the counts take between 8-14 days to recover, treatment may be re-started with a 50% dose reduction Delay treatment until the counts have recovered, the restart using a 50% dose reduction Hepatic Impairment Patients with hepatic impairment should be closely monitored for signs and symptoms of toxicity. Since chlorambucil is primarily metabolized in the liver, dose reduction should be considered in patients with severe hepatic impairment. However, there are insufficient data in patients with hepatic impairment to provide a specific dosing recommendation. Rituximab does not require dose adjustment in hepatic impairment. Renal Impairment Dose adjustment is not considered necessary in renal impaired patients. Patients with evidence of impaired renal function should be carefully monitored as they are prone to additional myelosuppression. Rituximab does not require dose adjustment in renal impairment. Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. In general for all other non-haematological NCI-CTC grade 3 and above toxicities delay treatment until the adverse effect has resolved to NCI-CTC grade 2 or below. The dose should then be reduced to 75% of the original dose. If toxicity recurs delay until recovery and further dose reduce to 50% of the original dose or discontinue as appropriate. Rituximab Infusion related adverse reactions have been observed in 10% of patients treated with rituximab. Version 1 (February 2017) Page 2 of 8 CLL-Chlorambucil (7 day)-Rituximab (Split) Rituximab administration is associated with the onset of cytokine release syndrome. This condition is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. It may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, acute renal failure, elevated lactate dehydrogenase (LDH) and can lead to acute respiratory failure and death. This effect on the lungs may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. Cytokine release syndrome frequently occurs within one or two hours of initiating the first infusion. Hypersensitivity reactions, including anaphylaxis, have been reported following the intravenous administration of proteins. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes of starting the infusion. Medicinal products for the treatment of allergic reactions should be available for immediate use in the event of hypersensitivity developing during the administration of rituximab. Use of rituximab may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening neurological, cognitive or psychiatric symptoms that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed the rituximab must be permanently discontinued. Regimen 28 day cycle for 12 cycles Cycle 1 Drug Chlorambucil Rituximab Rituximab Dose 10mg/m2 once a day 100mg 325mg/m2 Days Administration 1, 2, 3, 4, 5, 6, 7 Oral 1 Intravenous infusion in 50ml sodium chloride 0.9% over 120 minutes Intravenous infusion in 500ml sodium chloride 0.9% at a rate of 50mg/hour 2 increasing by 50mg/hour every 30 minutes if tolerated to a maximum rate of 400mg/hour Cycle 2, 3, 4, 5, 6 Drug Chlorambucil Rituximab Dose 10mg/m2 once a day 500mg/m2 Days Administration 1, 2, 3, 4, 5, 6, 7 Oral Intravenous infusion in 500ml sodium 1 chloride 0.9% as per your local rituximab administration guidelines* *If the lymphocyte is greater than 25x109/L on day one then consider fractionating the dose of rituximab as follows; Version 1 (February 2017) Page 3 of 8 CLL-Chlorambucil (7 day)-Rituximab (Split) Day 1 - rituximab 125mg/m2 in 100ml sodium chloride 0.9% Day 2 - rituximab 375mg/m2 in 500ml sodium chloride 0.9% If there were no problems with the previous infusion then start both fractions at 100mg/hour and escalate the rate in 100mg/hour increments every 30 minutes to a maximum rate of 400mg/hour. If reactions occurred with the previous cycle, give both fractions starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour Cycle 7, 8, 9, 10, 11, 12 Cycle 7 onwards should only be considered for those individual who demonstrate a continuing response to treatment. Drug Dose Chlorambucil 10mg/m2 once a day Days 1, 2, 3, 4, 5, 6, 7 Administration Oral Dose Information • Chlorambucil is available as 2mg film-coated tablets. • The dose of rituximab for the 50mg/m2 - 125mg/m2 dose will be rounded as per the national dose bands (10mg/ml) • The dose of rituximab from 325mg/m2 and above will be dose rounded to the nearest 100mg (up if halfway) Administration Information • Chlorambucil should be swallowed whole on an empty stomach either one hour before meals or three hours after. • The daily dose may be divided into three (morning, noon and night) if nausea or vomiting is problematic. • The film-coated tablets should not be crushed or dissolved prior to administration. • The rate of administration of rituximab varies. Please refer to the rituximab administration guidelines. Additional Therapy • No routine anti-emetics are required. They may be added from “favourites” on ARIA for individual patients who may require treatment for nausea and vomiting. • Rituximab pre-medication 30 minutes prior to rituximab - chlorphenamine 10mg intravenous - hydrocortisone 100mg intravenous - paracetamol 1000mg oral Version 1 (February 2017) Page 4 of 8 CLL-Chlorambucil (7 day)-Rituximab (Split) • Rituximab infusion reactions - hydrocortisone 100mg intravenous when required for rituximab infusion related reactions - salbutamol 2.5mg nebule when required for rituximab related bronchospasm - consider pethidine 25-50mg intravenous bolus for rituximab related rigors that fail to respond to steroids. • Patients with CLL are at risk of tumour lysis syndrome (TLS). The British Society of Haematology guidelines are a useful reference source. Oral allopurinol is one option for prophylaxis (300mg once a day oral for 7 days in he first cycle will be set in ARIA). Intravenous rasburicase can be considered in high risk individuals. • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. Additional Information • The National Patient Safety Alert on oral chemotherapy (NPSA/2008/RRR001) must be followed in relation to chlorambucil. • It must be made clear to all staff, including those in the community, that chlorambucil is given as a short course that is repeated and should only be prescribed under the supervision of a consultant haematologist. Coding • Procurement – X71.3 • Delivery – X72.2, X72.4 References 1. Foa R, Del Gludice I, Cuneo A et al. Chlorambucil plus rituximab with or without maintenance rituximab as first line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol 2014; 89 (5): 480-486. 2. Cramer P, Isfort S, Bahlo J et al. Outcome of advanced chronic lymphocytic leukemia following different first line and relapse therapies: a meta-analysis of five prospective trials by the German CLL Study Group. Haematologica 2015; 100 (11): 1451-9. Version 1 (February 2017) Page 5 of 8 CLL-Chlorambucil (7 day)-Rituximab (Split) REGIMEN SUMMARY Cycle 1 Chlorambucil (7 day)-Rituximab (Split) Day 1 1. Chlorphenamine 10mg intravenous 2. Hydrocortisone 100mg intravenous 3. Paracetamol 1000mg oral 4. Rituximab 100mg intravenous infusion in 50ml sodium chloride 0.9% over 120 minutes 5. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 6. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Day 2 7. Chlorphenamine 10mg intravenous 8. Hydrocortisone 100mg intravenous 9. Paracetamol 1000mg oral 10. Rituximab 325mg/m2 intravenous infusion in 500ml sodium chloride 0.9% Administration Guidelines Start at a rate of 50mg/hour and, if tolerated, increase by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour. 11. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 12. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Take Home Medicines (day one only) 13. Chlorambucil 10mg/m2 once a day for 7 days starting on day 1 of the cycle oral Administration Information Oral chemotherapy. Start on day 1 of the chemotherapy cycle. Swallow whole, do not crush or chew. Take on an empty stomach either an hour before food or three hours after. The daily dose may be divided into three (morning, noon and night) if adverse effects such as nausea and vomiting occur. 14. Allopurinol 300mg once a day for 7 days oral Version 1 (February 2017) Page 6 of 8 CLL-Chlorambucil (7 day)-Rituximab (Split) Cycles 2, 3, 4, 5, 6 Day 1 15. Chlorphenamine 10mg intravenous 16. Hydrocortisone 100mg intravenous 17. Paracetamol 1000mg oral 18. Rituximab 500mg/m2 intravenous infusion in 500ml sodium chloride 0.9% Administration Instructions Administer as per your local administration guidelines If the lymphocyte is greater than 25x109/L on day one then consider fractionating the dose of rituximab as follows; Day 1 - rituximab 125mg/m2 in 100ml sodium chloride 0.9% Day 2 - rituximab 375mg/m2 in 500ml sodium chloride 0.9% If there were no problems with the previous infusion then start both fractions at 100mg/hour and escalate the rate in 100mg/hour increments every 30 minutes to a maximum rate of 400mg/hour. If reactions occurred with the previous cycle, give both fractions starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour 19. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 20. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Take Home Medicines (day one only) 21. Chlorambucil 10mg/m2 once a day for 7 days starting on day 1 of the cycle oral Administration Information Oral chemotherapy. Start on day 1 of the chemotherapy cycle. Swallow whole, do not crush or chew. Take on an empty stomach either an hour before food or three hours after. The daily dose may be divided into three (morning, noon and night) if adverse effects such as nausea and vomiting occur. Cycles 7, 8, 9, 10, 11, 12 Take Home Medicines (day one only) 22. Chlorambucil 10mg/m2 once a day for 7 days starting on day 1 of the cycle oral Administration Information Oral chemotherapy. Start on day 1 of the chemotherapy cycle. Swallow whole, do not crush or chew. Take on an empty stomach either an hour before food or three hours after. The daily dose may be divided into three (morning, noon and night) if adverse effects such as nausea and vomiting occur. Version 1 (February 2017) Page 7 of 8 CLL-Chlorambucil (7 day)-Rituximab (Split) DOCUMENT CONTROL Version Date Amendment Written By Approved By 1 February 2017 None Dr Deborah Wright Pharmacist Dr Helen Dignum Consultant Haematologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. Version 1 (February 2017) Page 8 of 8 CLL-Chlorambucil (7 day)-Rituximab (Split)
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/CLL/Chlorambucil-7-Rituximab-Split.pdf

Chlorambucil_2_Obinutuzumab

Description: Chemotherapy Protocol Chronic Lymphocytic Leukaemia Chlorambucil (2 day)-Obinutuzumab (6 cycles) Regimen • CLL – Chlorambucil (2 day)-Obinutuzumab Indication • The first line treatment of CLL in those with co-morbidities making them unsuitable for full dose fludarabine therapy or bendamustine treatment. • Palliative intent Toxicity Drug Chlorambucil Obinutuzumab Adverse Effect Neutropenia, thrombocytopenia, anaemia, nausea, vomiting, diarrhoea, mouth ulceration, rash Infusion related reactions, Progressive multifocal leukoencephalopathy (PML), cardiac toxicity, thrombocytopenia, neutropenia, tumour lysis syndrome The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring • FBC on day one, optional on days eight and fifteen of the cycle • U&E and LFT prior to day one and optionally fifteen of the cycle • Hepatitis B status prior to starting treatment. Patients with positive hepatitis B serology should consult a liver disease expert before the start of treatment and should be monitored and managed following local medical standards to prevent hepatitis re-activation • Consider uric acid and bone profile prior to cycle one in those considered at risk of tumour lysis syndrome Dose Modifications The dose modifications listed are for haematological, liver and renal function and drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Version 1.1 (October 2017) Page 1 of 14 CLL-Chlorambucil (2 day)-Obinutuzumab (6 cycles) Haematological Dose modifications for haematological toxicity in the table below are for general guidance only. Always refer to the responsible consultant as any dose reductions or delays will be dependent on clinical circumstances and treatment intent. Consider blood transfusion or the use of erythropoietin according to NICE TA323 if the patient is symptomatic of anaemia or where the haemoglobin is less than 8g/dL. At the start of each cycle the neutrophil count should be equal to or greater that 1x109/L and the platelets equal to or greater than 100x109/L. Toxicity Obinutuzumab Dose Grade 3 or 4 haematological toxicity, febrile neutropenia or Hold until the above thrombocytopenic bleeding parameters are met then that delays treatment by less restart at usual dose. than 4 weeks Chlorambucil Dose (% of previous dose) Hold until the above parameters are met. 1st episode: upon recovery restart at 75% 2nd episode: upon recovery restart at 50% Grade 3 or 4 haematological toxicity that delays treatment Discontinue by more than 4 weeks 3rd episode: discontinue Discontinue Hepatic Impairment Patients with hepatic impairment should be closely monitored for signs and symptoms of toxicity. Since chlorambucil is primarily metabolized in the liver, dose reduction should be considered in patients with severe hepatic impairment. However, there are insufficient data in patients with hepatic impairment to provide a specific dosing recommendation. The safety and efficacy of obinutuzumab in patients with impaired hepatic function has not been established. Renal Impairment Dose adjustment is not considered necessary for either chlorambucil or obinutuzumab in those with mild to moderate renal impairment. Patients with evidence of impaired renal function should be carefully monitored as they are prone to additional myelosuppression. Version 1.1 (October 2017) Page 2 of 14 CLL-Chlorambucil (2 day)-Obinutuzumab (6 cycles) Other Toxicity Obinutuzumab Chlorambucil dose dose (% previous dose) Grade 2 or 3 related organ/non- haematological toxicity Hold until less than or equal to grade 1 Hold until less than or equal to grade 1 Grade 2 non haematological toxicity that delays treatment by more than 4 weeks Discontinue Discontinue Grade 4 related organ/non- haematological toxicity, severe haemorrhage, severe skin reaction, pneumonitis, severe arrhythmias or Discontinue Discontinue other severe cardiovascular events Viral hepatitis or other serious infections; reactivation of hepatitis B Discontinue Discontinue Obinutuzumab Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with obinutuzumab. The diagnosis of PML should be considered in any patient presenting with new-onset or changes to pre- existing neurologic manifestations. The patient should be referred to a neurologist for the evaluation and treatment of PML. Infusion Reactions Obinutuzumab administration is associated with infusion related reactions, particularly during the first cycle. Most frequently reported symptoms associated with an infusion related reaction were nausea, chills, hypotension, pyrexia, vomiting, dyspnoea, flushing, hypertension, headache, tachycardia, and diarrhoea. Respiratory and cardiac symptoms such as bronchospasm, larynx and throat irritation, wheezing, laryngeal oedema and atrial fibrillation have also been reported. Anaphylaxis has been reported during administration of obinutuzumab. If a hypersensitivity reaction is suspected during infusion (e.g. symptoms typically occurring after previous exposure and very rarely with the first infusion), the infusion must be stopped and treatment permanently discontinued. Appropriate pre-medication must be administered before each infusion to reduce the risk of infusion related reactions. Infusion related reactions should be treated as described in the table below. Version 1.1 (October 2017) Page 3 of 14 CLL-Chlorambucil (2 day)-Obinutuzumab (6 cycles) Toxicity Grade Obinutuzumab Chlorambucil Dose (% of previous dose) Reduce the infusion rate by half and treat symptoms. Restart the infusion once 1-2 symptoms have resolved. Escalate infusion rate No change as tolerated at increments appropriate for treatment Hold infusion and treat the symptoms. Restart the 1episode of grade 3 infusion once the symptoms have resolved at no more than half the previous rate. Escalate the infusion rate as tolerated at increments appropriate for the treatment dose (see below) The day 1 (cycle 1) infusion rate may be increased back up to 25mg/hr after 60 minutes, but not increased further No change 2nd episode of grade 3 (during same or subsequent Infusion must be stopped and permanently discontinued therapy must be infusion) Discontinue Grade 4 or acute life threatening respiratory Infusion must be stopped and therapy must be permanently discontinued Discontinue reactions Tumour Lysis Syndrome (TLS) Tumour lysis syndrome (TLS) has been reported with obinutuzumab. Patients who are considered to be at risk of TLS (e.g. patients with a high tumour burden and/or a high circulating lymphocyte count (greater than 25x109/L) and/or renal impairment (CrCl less than 70 ml/min) should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of allopurinol or a suitable alternative such as rasburicase starting 12-24 hours prior to the infusion. All patients considered at risk should be carefully monitored during the initial days of treatment with a special focus on renal function, potassium, and uric acid values. Any additional guidelines according to standard practice should be followed. For example the BTS guidelines. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. Regimen 28 day cycle for 6 cycles for treatment and 12 cycles for maintenance (6 cycles will be set in ARIA) Please note that if you add additional cycles to this regimen using the pen icon you must do this as starting from the last cycle of treatment (eg cycle 6). If you choose start from cycle one then the first cycle with the different doses of obintuzumab will be added. Version 1.1 (October 2017) Page 4 of 14 CLL-Chlorambucil (2 day)-Obinutuzumab (6 cycles) Cycle 1 Drug Chlorambucil Obinutuzumab Dose 0.5mg/kg 100mg Obinutuzumab 900mg Obinutuzumab 1000mg Days 1, 15 1 2 8, 15 Administration Oral Intravenous infusion in 100ml sodium chloride 0.9% at a rate of 25mg/hour (over 240 minutes)* Intravenous infusion in 250ml sodium chloride 0.9% at a rate of 50mg/hour* Intravenous infusion in 250ml sodium chloride 0.9% at a rate of 100mg/hour* Cycle 2, 3, 4, 5, 6 Drug Chlorambucil Obinutuzumab Dose 0.5mg/kg 1000mg Days 1, 15 1 Administration Oral Intravenous infusion in 250ml sodium chloride 0.9% at a rate of 100mg/hour* *Please see administration information below for infusion rates Dose Information • Chlorambucil is available as 2mg film-coated tablets. Administration Information • Chlorambucil should be swallowed whole on an empty stomach either one hour before meals or three hours after. • The daily dose may be divided into three (morning, noon and night) or the full dose taken at night if nausea or vomiting is problematic. • The film-coated chlorambucil tablets should not be crushed or dissolved prior to administration. • Obinutuzumab standard infusion rates, in the absence of reactions are as follows; Version 1.1 (October 2017) Page 5 of 14 CLL-Chlorambucil (2 day)-Obinutuzumab (6 cycles) Cycle Day of Treatment Rate of Infusion 1 Day 1 Administer at 25mg/hour (over 240 minutes). Do not (100mg in 100ml) increase the rate 1 Day 2 (or day 1 continued) (900mg in 250ml) Start the administration at 50mg/hour The rate of the infusion can be escalated in increments 50 mg/hour every 30 minutes to a maximum rate of 400mg/hour of Day 8, 15 Infusions can be started at a rate of 100mg/hour and 1 increased by 100 mg/hour increments every 30 minutes to (1000mg in 250ml) a maximum of 400mg/hour 2 onwards All days (1000mg in 250ml) Infusions can be started at a rate of 100mg/hour and increased by 100mg/hour increments every 30 minutes to a maximum of 400mg/hour The recommended dose of obinutuzumab is 1000 mg administered over day 1 and day 2, and on day 8 and day 15 of the first treatment cycle. Two infusion bags should be prepared for the infusion on days 1 and 2 (100 mg for day 1 and 900 mg for day 2). If the first infusion (100mg) is completed without modifications of the infusion rate or interruptions, the second bag may be administered on the same day (no dose delay necessary, no repetition of premedication), provided that appropriate time, conditions and medical supervision are available throughout the infusion. If there are any modifications of the infusion rate or interruptions during the first 100 mg the second infusion (900mg) must be administered the following day. Additional Treatment • Antiemetics 15-30 minutes prior to chemotherapy - metoclopramide 10mg three times a day when required • Premedication for obinutuzumab infusion reactions - sodium chloride 0.9% 500ml intravenous infusion over 60 minutes then as follows; Version 1.1 (October 2017) Page 6 of 14 CLL-Chlorambucil (2 day)-Obinutuzumab (6 cycles) Cycle 1 days 1 and 2 Cycle 1 days 8 and 15 and Cycles 2, 3, 4, 5, 6 Pre-medication (60 minutes prior to obinutuzumab) All Patients Patients without infusion related reactions Methylprednisolone sodium succinate √ 80mg intravenous Chlorphenamine √ 10mg intravenous Paracetamol 1000mg oral √ √ Patients with grades 1-2 infusion related reactions Patients with a grade 3 infusion related reactions or with a lymphocyte count greater than 25x109/L √ √ √ √ √ On an as required basis; - chlorphenamine 10mg intravenous for infusion reactions - lorazepam 1mg oral for rigors - methylprednisolone sodium succinate 80mg intravenous for infusion reactions - paracetamol 1000mg oral for pyrexia - pethidine 25mg intravenous in 10ml sodium chloride 0.9% over 5 minutes for rigors following a verbal confirmation to administer from a doctor. • Allopurinol 300mg oral starting two days prior to day one cycle one for 7 days in total (not included in ARIA). Rasburicase may be required for high risk individuals. • Anti-infective prophylaxis as follows; - consider aciclovir 400mg twice a day oral (consultants discretion, not included on ARIA) • Mouthwashes as per local formulary Additional Information • The National Patient Safety Alert on oral chemotherapy (NPSA/2008/RRR001) must be followed in relation to chlorambucil. • It must be made clear to all staff, including those in the community, that chlorambucil is given as a short course that is repeated and should only be Version 1.1 (October 2017) Page 7 of 14 CLL-Chlorambucil (2 day)-Obinutuzumab (6 cycles) prescribed under the supervision of a consultant haematologist. • Hypotension may occur during obinutuzumab intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each obinutuzumab infusion and for the first hour after administration. Patients at acute risk of hypertensive crisis should be evaluated for the benefits and risks of withholding their anti-hypertensive medicine Coding • Procurement – X71.5 • Delivery – X72.1, X72.4 References 1. Goede V, Fisher K, Busch et al. Obinutuzumab plus chlorambucil in patients with chronic lymphocytic leukemia and coexisting conditions. N Engl J Med 2014; 370 (12): 1101-1110. 2. Dawson K, Moran M, Guindon K et al. Managing infusion related reactions for patients with chronic lymphocytic leukemia receiving obinutuzumab . Clin J Oncol Nursing 2016; 20 (2): 41-48 Version 1.1 (October 2017) Page 8 of 14 CLL-Chlorambucil (2 day)-Obinutuzumab (6 cycles) REGIMEN SUMMARY Chlorambucil (2 day)-Obinutuzumab (6 cycles) Cycle 1 Day 1 1. Sodium chloride 0.9% 500ml intravenous infusion over 60 minutes 2. Chlorphenamine 10mg intravenous Administration Instructions Administer 60 minutes prior to obinutuzumab 3. Methylprednisolone sodium succinate 80mg intravenous Administration Instructions Administer 60 minutes prior to obinutuzumab 4. Paracetamol 1000mg oral Administration Instructions Please check if the patient takes regular paracetamol for pain control and take dose into account Administer 60 minutes prior to obinutuzumab 5. Obinutuzumab 100mg intravenous infusion in 100ml sodium chloride 0.9% over 240 minutes Administration Instructions Please refer to the protocol for information regarding infusion rates and infusion related reactions. These may be increased according to tolerance as per the protocol. 6. Chlorphenamine 10mg when required for infusion related reactions Administration Instructions For the relief of infusion related reactions 7. Lorazepam 1mg oral when required for rigors Administration Instructions For the relief of rigors 8. Methylprednisolone sodium succinate 80mg intravenous bolus when required for the relief of infusion related reactions Administration Instructions For the relief of infusion related reactions 9. Paracetamol 1000mg oral when required for pyrexia Administration Instructions For the relief of pyrexia. Please check if the patient takes regular paracetamol for pain control and take dose into account 10. Pethidine 25mg intravenous bolus in 10ml sodium chloride 0.9% over 5 minutes for the relief of rigors Administration Instructions For the relief of rigors following a verbal confirmation to administer from a doctor Day 2 11. Sodium chloride 0.9% 500ml intravenous infusion over 60 minutes 12. Chlorphenamine 10mg intravenous Administration Instructions Version 1.1 (October 2017) Page 9 of 14 CLL-Chlorambucil (2 day)-Obinutuzumab (6 cycles) Administer 60 minutes prior to obinutuzumab 13. Methylprednisolone sodium succinate 80mg intravenous Administration Instructions Administer 60 minutes prior to obinutuzumab 14. Paracetamol 1000mg oral Administration Instructions Please check if the patient takes regular paracetamol for pain control and take dose into account Administer 60 minutes prior to obinutuzumab 15. Obinutuzumab 900mg intravenous infusion in 250ml sodium chloride 0.9% Administration Instructions Please refer to the protocol for information regarding infusion rates and infusion related reactions. These may be increased according to tolerance as per the protocol. 16. Chlorphenamine 10mg when required for infusion related reactions Administration Instructions For the relief of infusion related reactions 17. Lorazepam 1mg oral when required for rigors Administration Instructions For the relief of rigors 18. Methylprednisolone sodium succinate 80mg intravenous bolus when required for the relief of infusion related reactions Administration Instructions For the relief of infusion related reactions 19. Paracetamol 1000mg oral when required for pyrexia Administration Instructions For the relief of pyrexia. Please check if the patient takes regular paracetamol for pain control and take dose into account 20. Pethidine 25mg intravenous bolus in 10ml sodium chloride 0.9% over 5 minutes for the relief of rigors Administration Instructions For the relief of rigors following a verbal confirmation to administer from a doctor Day 8 21. Sodium chloride 0.9% 500ml intravenous infusion over 60 minutes 22. Chlorphenamine 10mg intravenous when required for infusion related reactions Administration Instructions Please refer to the protocol. Administer 60 minutes prior to obinutuzumab if there has been a grade 1 or above infusion related reaction or with a lymphocyte count than 25x109/L 23. Methylprednisolone sodium succinate 80mg intravenous when required for infusion related reactions Administration Instructions Please refer to the protocol. Administer 60 minutes prior to obinutuzumab if there has been a grade 3 or above infusion related reaction 24. Paracetamol 1000mg oral Administration Instructions Please check if the patient takes regular paracetamol for pain control and take dose into account. Administer 60 minutes prior to obinutuzumab 25. Obinutuzumab 1000mg intravenous infusion in 250ml sodium chloride 0.9% Administration Instructions Please refer to the protocol for information regarding infusion rates and infusion related reactions. These may be increased according to tolerance as per the protocol. Version 1.1 (October 2017) Page 10 of 14 CLL-Chlorambucil (2 day)-Obinutuzumab (6 cycles) 26. Chlorphenamine 10mg when required for infusion related reactions Administration Instructions For the relief of infusion related reactions or with a lymphocyte count greater than 25x109/L 27. Lorazepam 1mg oral when required for rigors Administration Instructions For the relief of rigors 28. Methylprednisolone sodium succinate 80mg intravenous bolus when required for the relief of infusion related reactions Administration Instructions For the relief of infusion related reactions 29. Paracetamol 1000mg oral when required for pyrexia Administration Instructions For the relief of pyrexia. Please check if the patient takes regular paracetamol for pain control and take dose into account 30. Pethidine 25mg intravenous bolus in 10ml sodium chloride 0.9% over 5 minutes for the relief of rigors Administration Instructions For the relief of rigors following a verbal confirmation to administer from a doctor Day 15 31. Sodium chloride 0.9% 500ml intravenous infusion over 60 minutes 32. Chlorphenamine 10mg intravenous when required for infusion related reactions Administration Instructions Please refer to the protocol. Administer 60 minutes prior to obinutuzumab if there has been a grade 1 or above infusion related reaction or with a lymphocyte count greater than 25x109/L 33. Methylprednisolone sodium succinate 80mg intravenous when required for infusion related reactions Administration Instructions Please refer to the protocol. Administer 60 minutes prior to obinutuzumab if there has been a grade 3 or above infusion related reaction 34. Paracetamol 1000mg oral Administration Instructions Please check if the patient takes regular paracetamol for pain control and take dose into account. Administer 60 minutes prior to obinutuzumab 35. Obinutuzumab 1000mg intravenous infusion in 250ml sodium chloride over 240 minutes Administration Instructions Please refer to the protocol for information regarding infusion rates and infusion related reactions. These may be increased according to tolerance as per the protocol. 36. Chlorphenamine 10mg when required for infusion related reactions Administration Instructions For the relief of infusion related reactions or with a lymphocyte count greater than 25x109/L 37. Lorazepam 1mg oral when required for rigors Administration Instructions For the relief of rigors Version 1.1 (October 2017) Page 11 of 14 CLL-Chlorambucil (2 day)-Obinutuzumab (6 cycles) 38. Methylprednisolone sodium succinate 80mg intravenous bolus when required for the relief of infusion related reactions Administration Instructions For the relief of infusion related reactions 39. Paracetamol 1000mg oral when required for pyrexia Administration Instructions For the relief of pyrexia. Please check if the patient takes regular paracetamol for pain control and take dose into account 40. Pethidine 25mg intravenous bolus in 10ml sodium chloride 0.9% over 5 minutes for the relief of rigors Administration Instructions For the relief of rigors following a verbal confirmation to administer from a doctor Take Home Medicines (day one only) 41. Chlorambucil 0.5mg/kg on days 1 and 15 only oral Administration Information Oral chemotherapy. Please supply day 1 and day 15 on day 1. Swallow whole, do not crush or chew. Take on an empty stomach either one hour before food or three hours after. The daily dose may be divided into three (morning, noon and night) or the full dose taken at night if adverse effects such as nausea and vomiting occur. 42. Metoclopramide 10mg three times a day when required for the relief of nausea Administration Instructions Please supply 28 tablets or nearest original pack size Cycle 2, 3, 4, 5, 6 Day 1 43. Sodium chloride 0.9% 500ml intravenous infusion over 60 minutes 44. Chlorphenamine 10mg intravenous when required for infusion related reactions Administration Instructions Please refer to the protocol. Administer 60 minutes prior to obinutuzumab if there has been a grade 1 or above infusion related reaction 45. Methylprednisolone sodium succinate 80mg intravenous when required for infusion related reactions Administration Instructions Please refer to the protocol. Administer 60 minutes prior to obinutuzumab if there has been a grade 3 or above infusion related reactions 46. Paracetamol 1000mg oral Administration Instructions Please check if the patient takes regular paracetamol for pain control and take dose into account. Administer 60 minutes prior to obinutuzumab 47. Obinutuzumab 1000mg intravenous infusion in 250ml sodium chloride 0.9% Administration Instructions Please refer to the protocol for information regarding infusion rates and infusion related reactions. These may be increased according to tolerance as per the protocol. 48. Chlorphenamine 10mg when required for infusion related reactions Administration Instructions For the relief of infusion related reactions or with a lymphocyte count greater than 25x109/L 49. Lorazepam 1mg oral when required for rigors Administration Instructions Version 1.1 (October 2017) Page 12 of 14 CLL-Chlorambucil (2 day)-Obinutuzumab (6 cycles) For the relief of rigors 50. Methylprednisolone sodium succinate 80mg intravenous bolus when required for the relief of infusion related reactions Administration Instructions For the relief of infusion related reactions 51. Paracetamol 1000mg oral when required for pyrexia Administration Instructions For the relief of pyrexia. Please check if the patient takes regular paracetamol for pain control and take dose into account 52. Pethidine 25mg intravenous bolus in 10ml sodium chloride 0.9% over 5 minutes for the relief of rigors Administration Instructions For the relief of rigors following a verbal confirmation to administer from a doctor Take Home Medicines (day one only) 53. Chlorambucil 0.5mg/kg on day 1 and 15 only oral Administration Information Oral chemotherapy. Please supply day 1 and day 15 on day 1. Swallow whole, do not crush or chew. Take on an empty stomach either one hour before food or three hours after. The daily dose may be divided into three (morning, noon and night) or the full dose atken at night if adverse effects such as nausea and vomiting occur. 55. Metoclopramide 10mg three times a day when required for the relief of nausea Administration Instructions Please supply 28 tablets or nearest original pack size Version 1.1 (October 2017) Page 13 of 14 CLL-Chlorambucil (2 day)-Obinutuzumab (6 cycles) DOCUMENT CONTROL Version Date Amendment Written By Approved By 1.1 October 2017 Hepatitis B statement updated. Dr Deborah Wright TLS information added Pharmacist Donna Kimber Pharmacy Technician 1 February 2017 None Dr Deborah Wright Pharmacist Dr Helen Dignum Consultant Haematologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. Version 1.1 (October 2017) Page 14 of 14 CLL-Chlorambucil (2 day)-Obinutuzumab (6 cycles)
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/CLL/Chlorambucil-2-Obinutuzumab.pdf

Chlorambucil_14_Rituximab_Split

Description: Chemotherapy Protocol Chronic Lymphocytic Leukaemia (CLL) Chlorambucil (14 day)-Rituximab (Split) Regimen • CLL – Chlorambucil (14 day)-Rituximab (Split) Indication • Treatment of CLL in elderly patients for whom treatment with fludarabine and cyclophosphamide or chlorambucil and obinutuzumab or bendamustine is not considered appropriate, due to co-morbidities or performance status • Split dose rituximab is indicated where the lymphocyte count is greater than 25x109/L • Disease modification Toxicity Drug Chlorambucil Rituximab Adverse Effect Neutropenia, thrombocytopenia, anaemia, nausea, vomiting, diarrhoea, mouth ulceration, rash Severe cytokine release syndrome, increased incidence of infective complications, progressive multifocal leukoencephalopathy The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring • FBC, U&Es and LFTs on day one of the cycle • Hepatitis B status prior to starting treatment with rituximab Dose Modifications The dose modifications listed are for haematological, liver and renal function and drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Haematological Dose modifications for haematological toxicity in the table below are for general guidance only. Always refer to the responsible consultant as any dose reductions or delays will be dependent on clinical circumstances and treatment intent. Consider blood transfusion or the use of erythropoietin according to NICE TA323 if the patient is symptomatic of anaemia or where the haemoglobin is less than 8g/dL. Version 1 (February 2017) Page 1 of 8 CLL-Chlorambucil (14 day)-Rituximab (Split) The dose of rituximab is rarely adjusted for haematological parameters. Neutrophils (x109/L) more than 1 0.5 - 1 less than 0.5 and / or Platelets (x109/L) more than 75 and / or 50 - 75 and / or less than 50 Chlorambucil Dose 100% Delay treatment for one week. If counts recover treatment can be re-started. If the counts take between 8-14 days to recover, treatment may be re-started with a 50% dose reduction Delay treatment until the counts have recovered, the restart using a 50% dose reduction Hepatic Impairment Patients with hepatic impairment should be closely monitored for signs and symptoms of toxicity. Since chlorambucil is primarily metabolized in the liver, dose reduction should be considered in patients with severe hepatic impairment. However, there are insufficient data in patients with hepatic impairment to provide a specific dosing recommendation. Rituximab does not require dose adjustment in hepatic impairment. Renal Impairment Dose adjustment is not considered necessary in renal impaired patients. Patients with evidence of impaired renal function should be carefully monitored as they are prone to additional myelosuppression. Rituximab does not require dose adjustment in renal impairment. Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. In general for all other non-haematological NCI-CTC grade 3 and above toxicities delay treatment until the adverse effect has resolved to NCI-CTC grade 2 or below. The dose should then be reduced to 75% of the original dose. If toxicity recurs delay until recovery and further dose reduce to 50% of the original dose or discontinue as appropriate. Rituximab Infusion related adverse reactions have been observed in 10% of patients treated with rituximab. Version 1 (February 2017) Page 2 of 8 CLL-Chlorambucil (14 day)-Rituximab (Split) Rituximab administration is associated with the onset of cytokine release syndrome. This condition is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. It may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, acute renal failure, elevated lactate dehydrogenase (LDH) and can lead to acute respiratory failure and death. This effect on the lungs may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. Cytokine release syndrome frequently occurs within one or two hours of initiating the first infusion. Hypersensitivity reactions, including anaphylaxis, have been reported following the intravenous administration of proteins. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes of starting the infusion. Medicinal products for the treatment of allergic reactions should be available for immediate use in the event of hypersensitivity developing during the administration of rituximab. Use of rituximab may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening neurological, cognitive or psychiatric symptoms that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed the rituximab must be permanently discontinued. Regimen 28 day cycle for 12 cycles Cycle 1 Drug Chlorambucil Rituximab Dose 10mg once a day 100mg Rituximab 325mg/m2 Days 1 – 14 inclusive 1 2 Administration Oral Intravenous infusion in 50ml sodium chloride 0.9% over 120 minutes Intravenous infusion in 500ml sodium chloride 0.9% at a rate of 50mg/hour increasing by 50mg/hour every 30 minutes if tolerated to a maximum rate of 400mg/hour Cycle 2, 3, 4, 5, 6 Drug Dose Chlorambucil 10mg once a day Rituximab 500mg/m2 Days 1 – 14 inclusive 1 Administration Oral Intravenous infusion in 500ml sodium chloride 0.9% as per the rituximab infusion guidelines* *If the lymphocyte count is greater than 25x109/L on day one then consider fractionating the dose of rituximab as follows; Version 1 (February 2017) Page 3 of 8 CLL-Chlorambucil (14 day)-Rituximab (Split) Day 1 - rituximab 125mg/m2 in 100ml sodium chloride 0.9% Day 2 - rituximab 375mg/m2 in 500ml sodium chloride 0.9% If there were no problems with the cycle 1 infusions then start both fractions at 100mg/hour and escalate the rate in 100mg/hour increments every 30 minutes to a maximum rate of 400mg/hour. If reactions occurred with cycle 1, give both fractions as for day 2 of cycle 1. Cycle 7, 8, 9, 10, 11, 12 Cycle 7 onwards should only be considered for those individual who demonstrate a continuing response to treatment. Drug Chlorambucil Dose 10mg once a day Days 1 – 14 inclusive Administration Oral Dose Information • Chlorambucil is available as 2mg film-coated tablets. • The dose of rituximab for the 50mg/m2 - 125mg/m2 dose will be rounded as per the national dose bands (10mg/ml) • The dose of rituximab from 325mg/m2 and above will be dose rounded to the nearest 100mg (up if halfway) Administration Information • Chlorambucil should be swallowed whole on an empty stomach either one hour before meals or three hours after. • The daily dose may be divided into three (morning, noon and night) if nausea or vomiting is problematic. • The film-coated tablets should not be crushed or dissolved prior to administration. • The rate of administration of rituximab varies. Please refer to the rituximab administration guidelines. Additional Therapy • No routine anti-emetics are required. They may be added from “favourites” on ARIA for individual patients who may require treatment for nausea and vomiting. • Rituximab pre-medication 30 minutes prior to rituximab - chlorphenamine 10mg intravenous - hydrocortisone 100mg intravenous - paracetamol 1000mg oral • Rituximab infusion reactions Version 1 (February 2017) Page 4 of 8 CLL-Chlorambucil (14 day)-Rituximab (Split) - hydrocortisone 100mg intravenous when required for rituximab infusion related reactions - salbutamol 2.5mg nebule when required for rituximab related bronchospasm - consider pethidine 25-50mg intravenous bolus for rituximab related rigors that fail to respond to steroids. • Allopurinol 300mg once a day oral for 7 days of the first cycle only • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. Additional Information • The National Patient Safety Alert on oral chemotherapy (NPSA/2008/RRR001) must be followed in relation to chlorambucil. • It must be made clear to all staff, including those in the community, that chlorambucil is given as a short course that is repeated and should only be prescribed under the supervision of a consultant haematologist. Coding • Procurement – X71.3 • Delivery – X72.2 References 1. Foa R, Del Gludice I, Cuneo A et al. Chlorambucil plus rituximab with or without maintenance rituximab as first line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol 2014; 89 (5): 480-486. 2. Cramer P, Isfort S, Bahlo J et al. Outcome of advanced chronic lymphocytic leukemia following different first line and relapse therapies: a meta-analysis of five prospective trials by the German CLL Study Group. Haematologica 2015; 100 (11): 1451-9. Version 1 (February 2017) Page 5 of 8 CLL-Chlorambucil (14 day)-Rituximab (Split) REGIMEN SUMMARY Cycle 1 Chlorambucil (14 day)-Rituximab (Split) Day 1 1. Chlorphenamine 10mg intravenous 2. Hydrocortisone 100mg intravenous 3. Paracetamol 1000mg oral 4. Rituximab 100mg intravenous infusion in 50ml sodium chloride 0.9% over 120 minutes 5. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 6. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Day 2 7. Chlorphenamine 10mg intravenous 8. Hydrocortisone 100mg intravenous 9. Paracetamol 1000mg oral 10. Rituximab 325mg/m2 intravenous infusion in 500ml sodium chloride 0.9% Administration Guidelines Start at a rate of 50mg/hour and, if tolerated, increase by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour. 11. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 12. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Take Home Medicines (day one only) 13. Chlorambucil 10mg once a day for 14 days starting on day 1 of the cycle oral Administration Information Oral chemotherapy. Start on day 1 of the chemotherapy cycle. Swallow whole, do not crush or chew. Take on an empty stomach either an hour before food or three hours after. The daily dose may be divided into three (morning, noon and night) if adverse effects such as nausea and vomiting occur. 14. Allopurinol 300mg once a day for 7 days oral Version 1 (February 2017) Page 6 of 8 CLL-Chlorambucil (14 day)-Rituximab (Split) Cycles 2, 3, 4, 5, 6 Day 1 15. Chlorphenamine 10mg intravenous 16. Hydrocortisone 100mg intravenous 17. Paracetamol 1000mg oral 18. Rituximab 500mg/m2 intravenous infusion in 500ml sodium chloride 0.9% Administration Instructions Administer as per your local administration guidelines If the lymphocyte is greater than 25x109/L on day one then consider fractionating the dose of rituximab as follows; Day 1 - rituximab 125mg/m2 in 100ml sodium chloride 0.9% Day 2 - rituximab 375mg/m2 in 500ml sodium chloride 0.9% If there were no problems with the previous infusion then start both fractions at 100mg/hour and escalate the rate in 100mg/hour increments every 30 minutes to a maximum rate of 400mg/hour. If reactions occurred with the previous cycle, give both fractions starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour 19. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 20. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Take Home Medicines (day one only) 21. Chlorambucil 10mg once a day for 14 days starting on day 1 of the cycle oral Administration Information Oral chemotherapy. Start on day 1 of the chemotherapy cycle. Swallow whole, do not crush or chew. Take on an empty stomach either an hour before food or three hours after. The daily dose may be divided into three (morning, noon and night) if adverse effects such as nausea and vomiting occur. Cycles 7, 8, 9, 10, 11, 12 Take Home Medicines (day one only) 22. Chlorambucil 10mg once a day for 14 days starting on day 1 of the cycle oral Administration Information Oral chemotherapy. Start on day 1 of the chemotherapy cycle. Swallow whole, do not crush or chew. Take on an empty stomach either an hour before food or three hours after. The daily dose may be divided into three (morning, noon and night) if adverse effects such as nausea and vomiting occur. Version 1 (February 2017) Page 7 of 8 CLL-Chlorambucil (14 day)-Rituximab (Split) DOCUMENT CONTROL Version Date Amendment Written By Approved By 1 February 2017 None Dr Deborah Wright Pharmacist Dr Helen Dignum Consultant Haematologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. Version 1 (February 2017) Page 8 of 8 CLL-Chlorambucil (14 day)-Rituximab (Split)
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/CLL/Chlorambucil-14-Rituximab-Split.pdf

Chlorambucil_14_Obinutuzumab

Description: Chemotherapy Protocol Chronic Lymphocytic Leukaemia Chlorambucil (14 day)-Obinutuzumab (6 cycles) Regimen • CLL – Chlorambucil (14 day)-Obinutuzumab Indication • The first line treatment of CLL in those with co-morbidities making them unsuitable for full dose fludarabine therapy or bendamustine treatment. • Palliative intent Toxicity Drug Chlorambucil Obinutuzumab Adverse Effect Neutropenia, thrombocytopenia, anaemia, nausea, vomiting, diarrhoea, mouth ulceration, rash Infusion related reactions, Progressive multifocal leukoencephalopathy (PML), cardiac toxicity, thrombocytopenia, neutropenia, tumour lysis syndrome The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring • FBC on day one, optional on days eight and fifteen of the cycle • U&E and LFT prior to day one and optionally fifteen of the cycle • Hepatitis B status prior to starting treatment. Patients with positive hepatitis B serology should consult a liver disease expert before the start of treatment and should be monitored and managed following local medical standards to prevent hepatitis re-activation • Consider uric acid and bone profile prior to cycle one in those considered at risk of tumour lysis syndrome Dose Modifications The dose modifications listed are for haematological, liver and renal function and drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Version 1.1 (October 2017) Page 1 of 14 CLL-Chlorambucil (14 day)-Obinutuzumab (6 cycles) Haematological Dose modifications for haematological toxicity in the table below are for general guidance only. Always refer to the responsible consultant as any dose reductions or delays will be dependent on clinical circumstances and treatment intent. Consider blood transfusion or the use of erythropoietin according to NICE TA323 if the patient is symptomatic of anaemia or where the haemoglobin is less than 8g/dL. At the start of each cycle the neutrophil count should be equal to or greater that 1x109/L and the platelets equal to or greater than 100x109/L. Toxicity Obinutuzumab Dose Grade 3 or 4 haematological toxicity, febrile neutropenia or Hold until the above thrombocytopenic bleeding parameters are met then that delays treatment by less restart at usual dose. than 4 weeks Chlorambucil Dose (% of previous dose) Hold until the above parameters are met. 1st episode: upon recovery restart at 75% 2nd episode: upon recovery restart at 50% Grade 3 or 4 haematological toxicity that delays treatment Discontinue by more than 4 weeks 3rd episode: discontinue Discontinue Hepatic Impairment Patients with hepatic impairment should be closely monitored for signs and symptoms of toxicity. Since chlorambucil is primarily metabolized in the liver, dose reduction should be considered in patients with severe hepatic impairment. However, there are insufficient data in patients with hepatic impairment to provide a specific dosing recommendation. The safety and efficacy of obinutuzumab in patients with impaired hepatic function has not been established. Renal Impairment Dose adjustment is not considered necessary for either chlorambucil or obinutuzumab in those with mild to moderate renal impairment. Patients with evidence of impaired renal function should be carefully monitored as they are prone to additional myelosuppression. Version 1.1 (October 2017) Page 2 of 14 CLL-Chlorambucil (14 day)-Obinutuzumab (6 cycles) Other Toxicity Obinutuzumab Chlorambucil dose dose (% previous dose) Grade 2 or 3 related organ/non- haematological toxicity Hold until less than or equal to grade 1 Hold until less than or equal to grade 1 Grade 2 non haematological toxicity that delays treatment by more than 4 weeks Discontinue Discontinue Grade 4 related organ/non- haematological toxicity, severe haemorrhage, severe skin reaction, pneumonitis, severe arrhythmias or Discontinue Discontinue other severe cardiovascular events Viral hepatitis or other serious infections; reactivation of hepatitis B Discontinue Discontinue Obinutuzumab Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with obinutuzumab. The diagnosis of PML should be considered in any patient presenting with new-onset or changes to pre- existing neurologic manifestations. The patient should be referred to a neurologist for the evaluation and treatment of PML. Infusion Reactions Obinutuzumab administration is associated with infusion related reactions, particularly during the first cycle. Most frequently reported symptoms associated with an infusion related reaction were nausea, chills, hypotension, pyrexia, vomiting, dyspnoea, flushing, hypertension, headache, tachycardia, and diarrhoea. Respiratory and cardiac symptoms such as bronchospasm, larynx and throat irritation, wheezing, laryngeal oedema and atrial fibrillation have also been reported. Anaphylaxis has been reported during administration of obinutuzumab. If a hypersensitivity reaction is suspected during infusion (e.g. symptoms typically occurring after previous exposure and very rarely with the first infusion), the infusion must be stopped and treatment permanently discontinued. Appropriate pre-medication must be administered before each infusion to reduce the risk of infusion related reactions. Infusion related reactions should be treated as described in the table below. Version 1.1 (October 2017) Page 3 of 14 CLL-Chlorambucil (14 day)-Obinutuzumab (6 cycles) Toxicity Grade Obinutuzumab Chlorambucil Dose (% of previous dose) Reduce the infusion rate by half and treat symptoms. Restart the infusion once 1-2 symptoms have resolved. Escalate infusion rate No change as tolerated at increments appropriate for treatment Hold infusion and treat the symptoms. Restart the 1episode of grade 3 infusion once the symptoms have resolved at no more than half the previous rate. Escalate the infusion rate as tolerated at increments appropriate for the treatment dose (see below) The day 1 (cycle 1) infusion rate may be increased back up to 25mg/hr after 60 minutes, but not increased further No change 2nd episode of grade 3 (during same or subsequent Infusion must be stopped and permanently discontinued therapy must be infusion) Discontinue Grade 4 or acute life threatening respiratory Infusion must be stopped and therapy must be permanently discontinued Discontinue reactions Tumour Lysis Syndrome (TLS) Tumour lysis syndrome (TLS) has been reported with obinutuzumab. Patients who are considered to be at risk of TLS (e.g. patients with a high tumour burden and/or a high circulating lymphocyte count (greater than 25x109/L) and/or renal impairment (CrCl less than 70 ml/min) should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of allopurinol or a suitable alternative such as rasburicase starting 12-24 hours prior to the infusion. All patients considered at risk should be carefully monitored during the initial days of treatment with a special focus on renal function, potassium, and uric acid values. Any additional guidelines according to standard practice should be followed. For example the BTS guidelines. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. Regimen 28 day cycle for 6 cycles for treatment and 12 cycles for maintenance (6 cycles will be set in ARIA) Please note that if you add additional cycles to this regimen using the pen icon you must do this as starting from the last cycle of treatment (eg cycle 6). If you choose start from cycle one then the first cycle with the different doses of obintuzumab will be added. Version 1.1 (October 2017) Page 4 of 14 CLL-Chlorambucil (14 day)-Obinutuzumab (6 cycles) Cycle 1 Drug Chlorambucil Obinutuzumab Dose 10mg 100mg Obinutuzumab 900mg Obinutuzumab 1000mg Days 1 – 14 inclusive 1 2 8, 15 Administration Oral Intravenous infusion in 100ml sodium chloride 0.9% at a rate of 25mg/hour (over 240 minutes)* Intravenous infusion in 250ml sodium chloride 0.9% at a rate of 50mg/hour* Intravenous infusion in 250ml sodium chloride 0.9% at a rate of 100mg/hour* Cycle 2, 3, 4, 5, 6 Drug Chlorambucil Obinutuzumab Dose 10mg 1000mg Days 1 – 14 inclusive 1 Administration Oral Intravenous infusion in 250ml sodium chloride 0.9% at a rate of 100mg/hour* *Please see administration information below for infusion rates Dose Information • Chlorambucil is available as 2mg film-coated tablets. Administration Information • Chlorambucil should be swallowed whole on an empty stomach either one hour before meals or three hours after. • The daily dose may be divided into three (morning, noon and night) or the full dose given at night if nausea or vomiting is problematic. • The film-coated chlorambucil tablets should not be crushed or dissolved prior to administration. • Obinutuzumab standard infusion rates, in the absence of reactions are as follows; Version 1.1 (October 2017) Page 5 of 14 CLL-Chlorambucil (14 day)-Obinutuzumab (6 cycles) Cycle Day of Treatment Rate of Infusion 1 Day 1 Administer at 25mg/hour (over 240 minutes). Do not (100mg in 100ml) increase the rate 1 Day 2 (or day 1 continued) (900mg in 250ml) Start the administration at 50mg/hour The rate of the infusion can be escalated in increments 50 mg/hour every 30 minutes to a maximum rate of 400mg/hour of Day 8, 15 Infusions can be started at a rate of 100mg/hour and 1 increased by 100 mg/hour increments every 30 minutes to (1000mg in 250ml) a maximum of 400mg/hour 2 onwards All days (1000mg in 250ml) Infusions can be started at a rate of 100mg/hour and increased by 100mg/hour increments every 30 minutes to a maximum of 400mg/hour The recommended dose of obinutuzumab is 1000 mg administered over day 1 and day 2, and on day 8 and day 15 of the first treatment cycle. Two infusion bags should be prepared for the infusion on days 1 and 2 (100 mg for day 1 and 900 mg for day 2). If the first infusion (100mg) is completed without modifications of the infusion rate or interruptions, the second bag may be administered on the same day (no dose delay necessary, no repetition of premedication), provided that appropriate time, conditions and medical supervision are available throughout the infusion. If there are any modifications of the infusion rate or interruptions during the first 100 mg the second infusion (900mg) must be administered the following day. Additional Treatment • Antiemetics 15-30 minutes prior to chemotherapy - metoclopramide 10mg three times a day when required • Premedication for obinutuzumab infusion reactions - sodium chloride 0.9% 500ml intravenous infusion over 60 minutes then as follows; Version 1.1 (October 2017) Page 6 of 14 CLL-Chlorambucil (14 day)-Obinutuzumab (6 cycles) Cycle 1 days 1 and 2 Cycle 1 days 8 and 15 and Cycles 2, 3, 4, 5, 6 Pre-medication (60 minutes prior to obinutuzumab) All Patients Patients without infusion related reactions Methylprednisolone sodium succinate √ 80mg intravenous Chlorphenamine √ 10mg intravenous Paracetamol 1000mg oral √ √ Patients with grades 1-2 infusion related reactions Patients with a grade 3 infusion related reactions or with a lymphocyte count greater than 25x109/L √ √ √ √ √ On an as required basis; - chlorphenamine 10mg intravenous for infusion reactions - lorazepam 1mg oral for rigors - methylprednisolone sodium succinate 80mg intravenous for infusion reactions - paracetamol 1000mg oral for pyrexia - pethidine 25mg intravenous in 10ml sodium chloride 0.9% over 5 minutes for the relief of rigors following a verbal confirmation to administer from a doctor • Allopurinol 300mg oral starting two days prior to day one cycle one for 7 days (not included in ARIA). Patients with a high risk of TLS may require rasburicase. • Anti-infective prophylaxis as follows; - consider aciclovir 400mg twice a day oral (consultants discretion, not included on ARIA) • Mouthwashes as per local formulary Additional Information • The National Patient Safety Alert on oral chemotherapy (NPSA/2008/RRR001) must be followed in relation to chlorambucil. • It must be made clear to all staff, including those in the community, that chlorambucil is given as a short course that is repeated and should only be Version 1.1 (October 2017) Page 7 of 14 CLL-Chlorambucil (14 day)-Obinutuzumab (6 cycles) prescribed under the supervision of a consultant haematologist. • Hypotension may occur during obinutuzumab intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each obinutuzumab infusion and for the first hour after administration. Patients at acute risk of hypertensive crisis should be evaluated for the benefits and risks of withholding their anti-hypertensive medicine Coding • Procurement – X71.5 • Delivery – X72.1, X72.4 References 1. Goede V, Fisher K, Busch et al. Obinutuzumab plus chlorambucil in patients with chronic lymphocytic leukemia and coexisting conditions. N Engl J Med 2014; 370 (12): 1101-1110. 2. Dawson K, Moran M, Guindon K et al. Managing infusion related reactions for patients with chronic lymphocytic leukemia receiving obinutuzumab . Clin J Oncol Nursing 2016; 20 (2): 41-48 Version 1.1 (October 2017) Page 8 of 14 CLL-Chlorambucil (14 day)-Obinutuzumab (6 cycles) REGIMEN SUMMARY Chlorambucil (14 day)-Obinutuzumab (6 cycles) Cycle 1 Day 1 1. Sodium chloride 0.9% 500ml intravenous infusion over 60 minutes 2. Chlorphenamine 10mg intravenous Administration Instructions Administer 60 minutes prior to obinutuzumab 3. Methylprednisolone sodium succinate 80mg intravenous Administration Instructions Administer 60 minutes prior to obinutuzumab 4. Paracetamol 1000mg oral Administration Instructions Please check if the patient takes regular paracetamol for pain control and take dose into account Administer 60 minutes prior to obinutuzumab 5. Obinutuzumab 100mg intravenous infusion in 100ml sodium chloride 0.9% over 240 minutes Administration Instructions Please refer to the protocol for information regarding infusion rates and infusion related reactions. These may be increased according to tolerance as per the protocol. 6. Chlorphenamine 10mg when required for infusion related reactions Administration Instructions For the relief of infusion related reactions 7. Lorazepam 1mg oral when required for rigors Administration Instructions For the relief of rigors 8. Methylprednisolone sodium succinate 80mg intravenous bolus when required for the relief of infusion related reactions Administration Instructions For the relief of infusion related reactions 9. Paracetamol 1000mg oral when required for pyrexia Administration Instructions For the relief of pyrexia. Please check if the patient takes regular paracetamol for pain control and take dose into account 10. Pethidine 25mg intravenous bolus in 10ml sodium chloride 0.9% over 5 minutes for the relief of rigors Administration Instructions For the relief of rigors following a verbal confirmation to administer from a doctor Day 2 11. Sodium chloride 0.9% 500ml intravenous infusion over 60 minutes 12. Chlorphenamine 10mg intravenous Administration Instructions Administer 60 minutes prior to obinutuzumab Version 1.1 (October 2017) Page 9 of 14 CLL-Chlorambucil (14 day)-Obinutuzumab (6 cycles) 13. Methylprednisolone sodium succinate 80mg intravenous Administration Instructions Administer 60 minutes prior to obinutuzumab 14. Paracetamol 1000mg oral Administration Instructions Please check if the patient takes regular paracetamol for pain control and take dose into account Administer 60 minutes prior to obinutuzumab 15. Obinutuzumab 900mg intravenous infusion in 250ml sodium chloride 0.9% Administration Instructions Please refer to the protocol for information regarding infusion rates and infusion related reactions. These may be increased according to tolerance as per the protocol. 16. Chlorphenamine 10mg when required for infusion related reactions Administration Instructions For the relief of infusion related reactions. 17. Lorazepam 1mg oral when required for rigors Administration Instructions For the relief of rigors 18. Methylprednisolone sodium succinate 80mg intravenous bolus when required for the relief of infusion related reactions Administration Instructions For the relief of infusion related reactions 19. Paracetamol 1000mg oral when required for pyrexia Administration Instructions For the relief of pyrexia. Please check if the patient takes regular paracetamol for pain control and take dose into account 20. Pethidine 25mg intravenous bolus in 10ml sodium chloride 0.9% over 5 minutes for the relief of rigors Administration Instructions For the relief of rigors following a verbal confirmation to administer from a doctor Day 8 21. Sodium chloride 0.9% 500ml intravenous infusion over 60 minutes 22. Chlorphenamine 10mg intravenous when required for infusion related reactions Administration Instructions Please refer to the protocol. Administer 60 minutes prior to obinutuzumab if there has been a grade 1 or above infusion related reaction or when the lymphocyte count is greater than 25x109/L. 23. Methylprednisolone sodium succinate 80mg intravenous when required for infusion related reactions Administration Instructions Please refer to the protocol. Administer 60 minutes prior to obinutuzumab if there has been a grade 3 or above infusion related reaction 24. Paracetamol 1000mg oral Administration Instructions Please check if the patient takes regular paracetamol for pain control and take dose into account. Administer 60 minutes prior to obinutuzumab 25. Obinutuzumab 1000mg intravenous infusion in 250ml sodium chloride 0.9% Administration Instructions Please refer to the protocol for information regarding infusion rates and infusion related reactions. These may be increased according to tolerance as per the protocol. Version 1.1 (October 2017) Page 10 of 14 CLL-Chlorambucil (14 day)-Obinutuzumab (6 cycles) 26. Chlorphenamine 10mg when required for infusion related reactions Administration Instructions For the relief of infusion related reactions 27. Lorazepam 1mg oral when required for rigors Administration Instructions For the relief of rigors 28. Methylprednisolone sodium succinate 80mg intravenous bolus when required for the relief of infusion related reactions Administration Instructions For the relief of infusion related reactions 29. Paracetamol 1000mg oral when required for pyrexia Administration Instructions For the relief of pyrexia. Please check if the patient takes regular paracetamol for pain control and take dose into account 30. Pethidine 25mg intravenous bolus in 10ml sodium chloride 0.9% over 5 minutes for the relief of rigors Administration Instructions For the relief of rigors following a verbal confirmation to administer from a doctor Day 15 31. Sodium chloride 0.9% 500ml intravenous infusion over 60 minutes 32. Chlorphenamine 10mg intravenous when required for infusion related reactions Administration Instructions Please refer to the protocol. Administer 60 minutes prior to obinutuzumab if there has been a grade 1 or above infusion related reaction or when the lymphocyte count is greater than 25x109/L. 33. Methylprednisolone sodium succinate 80mg intravenous when required for infusion related reactions Administration Instructions Please refer to the protocol. Administer 60 minutes prior to obinutuzumab if there has been a grade 3 or above infusion related reaction 34. Paracetamol 1000mg oral Administration Instructions Please check if the patient takes regular paracetamol for pain control and take dose into account. Administer 60 minutes prior to obinutuzumab 35. Obinutuzumab 1000mg intravenous infusion in 250ml sodium chloride over 240 minutes Administration Instructions Please refer to the protocol for information regarding infusion rates and infusion related reactions. These may be increased according to tolerance as per the protocol. 36. Chlorphenamine 10mg when required for infusion related reactions Administration Instructions For the relief of infusion related reactions 37. Lorazepam 1mg oral when required for rigors Administration Instructions For the relief of rigors 38. Methylprednisolone sodium succinate 80mg intravenous bolus when required for the relief of infusion related reactions Administration Instructions For the relief of infusion related reactions Version 1.1 (October 2017) Page 11 of 14 CLL-Chlorambucil (14 day)-Obinutuzumab (6 cycles) 39. Paracetamol 1000mg oral when required for pyrexia Administration Instructions For the relief of pyrexia. Please check if the patient takes regular paracetamol for pain control and take dose into account 40. Pethidine 25mg intravenous bolus in 10ml sodium chloride 0.9% over 5 minutes for the relief of rigors Administration Instructions For the relief of rigors following a verbal confirmation to administer from a doctor Take Home Medicines (day one only) 41. Chlorambucil 10mg for 14 days starting on day 1 of the chemotherapy cycle oral Administration Information Oral chemotherapy. Start on day 1 of the chemotherapy cycle. Swallow whole, do not crush or chew. Take on an empty stomach either one hour before food or three hours after. The daily dose may be divided into three (morning, noon and night) or the full dose given at night if adverse effects such as nausea and vomiting occur. 42. Metoclopramide 10mg three times a day when required for the relief of nausea Administration Instructions Please supply 28 tablets or nearest original pack size Cycle 2, 3, 4, 5, 6 Day 1 43. Sodium chloride 0.9% 500ml intravenous infusion over 60 minutes 44. Chlorphenamine 10mg intravenous when required for infusion related reactions Administration Instructions Please refer to the protocol. Administer 60 minutes prior to obinutuzumab if there has been a grade 1 or above infusion related reaction or when the lymphocyte count is greater than 25x109/L. 45. Methylprednisolone sodium succinate 80mg intravenous when required for infusion related reactions Administration Instructions Please refer to the protocol. Administer 60 minutes prior to obinutuzumab if there has been a grade 3 or above infusion related reaction 46. Paracetamol 1000mg oral Administration Instructions Please check if the patient takes regular paracetamol for pain control and take dose into account. Administer 60 minutes prior to obinutuzumab 47. Obinutuzumab 1000mg intravenous infusion in 250ml sodium chloride 0.9% Administration Instructions Please refer to the protocol for information regarding infusion rates and infusion related reactions. These may be increased according to tolerance as per the protocol. 48. Chlorphenamine 10mg when required for infusion related reactions Administration Instructions For the relief of infusion related reactions 49. Lorazepam 1mg oral when required for rigors Administration Instructions For the relief of rigors Version 1.1 (October 2017) Page 12 of 14 CLL-Chlorambucil (14 day)-Obinutuzumab (6 cycles) 50. Methylprednisolone sodium succinate 80mg intravenous bolus when required for the relief of infusion related reactions Administration Instructions For the relief of infusion related reactions 51. Paracetamol 1000mg oral when required for pyrexia Administration Instructions For the relief of pyrexia. Please check if the patient takes regular paracetamol for pain control and take dose into account 52. Pethidine 25mg intravenous bolus in 10ml sodium chloride 0.9% over 5 minutes for the relief of rigors Administration Instructions For the relief of rigors following a verbal confirmation to administer from a doctor Take Home Medicines (day one only) 53. Chlorambucil 10mg for 14 days starting on day 1 of the chemotherapy cycle oral Administration Information Oral chemotherapy. Start on day 1 of the chemotherapy cycle Swallow whole, do not crush or chew. Take on an empty stomach either one hour before food or three hours after. The daily dose may be divided into three (morning, noon and night) or the full dose given at night if adverse effects such as nausea and vomiting occur. 55. Metoclopramide 10mg three times a day when required for the relief of nausea Administration Instructions Please supply 28 tablets or nearest original pack size Version 1.1 (October 2017) Page 13 of 14 CLL-Chlorambucil (14 day)-Obinutuzumab (6 cycles) DOCUMENT CONTROL Version Date Amendment Written By Approved By 1.1 October 2017 Hepatitis B information extended. Tumour lysis information added. Dr Deborah Wright Pharmacist Donna Kimber Pharmacy Technician 1 February 2017 None Dr Deborah Wright Pharmacist Dr Helen Dignum Consultant Haematologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. Version 1.1 (October 2017) Page 14 of 14 CLL-Chlorambucil (14 day)-Obinutuzumab (6 cycles)
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/CLL/Chlorambucil-14-Obinutuzumab.pdf

Bendamustine_90_RituximabSplit

Description: Chemotherapy Protocol CHRONIC LYMPHOCYTIC LEUKAEMIA BENDAMUSTINE (90)-RITUXIMAB (Split) There are multiple versions of this protocol in use that vary depending on the indication. Please ensure you have the correct protocol for the relevant diagnosis. Regimen • CLL – Bendamustine (90)-Rituximab (Split) Indication • First line treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients for whom fludarabine combination chemotherapy is not appropriate • Second, third or fourth line treatment of B-CLL (unlicensed indication) • Split dose rituximab is indicated where the lymphocyte count is greater than 25x109/L Toxicity Drug Bendamustine Rituximab Adverse Effect Transfusion related GVHD, Gastro-intestinal disturbances, fatigue, insomnia, cardiac dysfunction, hypotension/hypertension, hypersensitivity reactions, hypokalaemia. Severe cytokine release syndrome, increased incidence of infective complications, progressive multifocal leukoencephalopathy Patients treated with bendamustine carry a lifelong risk of transfusion associated graft versus host disease (TA-GVHD). Where blood products are required these patients must receive only irradiated blood products for life. Local blood transfusion departments must be notified as soon as the decision to treat is made and the patient must be issued with an alert card to carry with them at all times. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Drugs • FBC, LFTs and U&Es prior to day one of treatment • Check hepatitis B status before starting rituximab • The presence of a viral upper respiratory tract infection prior to treatment may increase the risk of rituximab associated hepatotoxicity. Patients should be assessed for any cold or flu-like symptoms prior to treatment. Version 1.1 (July 2018) Page 1 of 10 CLL- Bendamustine (90)-Rituximab (Split) Dose Modifications The dose modifications listed are for haematological, liver and renal function and some drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. In principle all dose reductions due to adverse drug reactions should not be re-escalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Haematological Dose modifications for haematological toxicity in the table below are for general guidance only. Always refer to the responsible consultant as any dose reductions or delays will be dependent on clinical circumstances and treatment intent. Low counts can be a consequence of bone marrow infiltration as well as drug toxicity. Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL (80g/L). Irradiated blood products must be used. Neutrophils (x109/L) more than 1 100% Dose Modifications 0.5-1 less than 0.5 or febrile neutropenia Platelets (x109/L) Delay until recovery and then give 100% 1st occurrence - delay until recovery and give 75% of the original dose 2nd occurrence - delay until recovery and give 50% of the original dose Dose Modifications more than 100 100% 25-100 less than 25 or bleeding Delay until recovery and give 100% 1st occurrence - delay until recovery and give 75% of the original dose 2nd occurrence - delay until recovery and give 50% of the original dose Hepatic Impairment The approach may be different where abnormal liver function tests are due to disease. Drug Bendamustine Bilirubin (µmol/L) less than 21 21-51 more than 51 Dose (% of original dose) 100% 70% no information Rituximab N/A No dose adjustment needed Version 1.1 (July 2018) Page 2 of 10 CLL- Bendamustine (90)-Rituximab (Split) Renal Impairment Drug Bendamustine Creatinine Clearance (ml/min) more than 10 10 or less Dose (% of original dose) 100% no information Rituximab N/A No dose adjustment needed Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. Bendamustine Skin Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis have been reported in patients who received bendamustine and allopurinol simultaneously. If patients experience any skin reactions during treatment, they should be monitored closely and, in the case of any suspicion of the skin reaction evolving to a serious muco-cutaneous reaction, treatment with bendamustine should be withheld until complete resolution of the event or discontinued. Other potential causes of skin toxicity should be evaluated and suspected agents discontinued accordingly. Infusion Reactions Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials. Symptoms are generally mild and include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred. Patients must be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Measures to prevent severe reactions, including antihistamines, paracetamol and corticosteroids must be considered in subsequent cycles in patients who have previously experienced infusion related reactions. Potassium In patients with cardiac dysfunction ensure the potassium remains above 3.5mmol/L during treatment with bendamustine. Rituximab Infusion Reactions Infusion related adverse reactions have been observed in 10% of patients treated with rituximab. The administration of rituximab in those with a diagnosis of CLL is more complex than for lymphomas. The risk of an infusion related reaction is much greater. To prevent this reaction, the cycle one dose is split over two days. In general the higher the white cell count, the greater is the risk of a reaction. Version 1.1 (July 2018) Page 3 of 10 CLL- Bendamustine (90)-Rituximab (Split) Rituximab administration is associated with the onset of cytokine release syndrome. This condition is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. It may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, acute renal failure, elevated lactate dehydrogenase (LDH) and can lead to acute respiratory failure and death. This effect on the lungs may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. Cytokine release syndrome frequently occurs within one or two hours of initiating the first infusion. Hypersensitivity reactions, including anaphylaxis, have been reported following the intravenous administration of proteins. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes of starting the infusion. Medicinal products for the treatment of allergic reactions should be available for immediate use in the event of hypersensitivity developing during the administration of rituximab. Neurological Use of rituximab may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening neurological, cognitive or psychiatric symptoms that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed the rituximab must be permanently discontinued. Regimen 28 day cycle for 6 cycles Cycle 1 Drug Bendamustine Rituximab Rituximab Dose 90mg/m2 100mg 325mg/m2 Days 1, 2 1 2 Administration Intravenous infusion in sodium chloride 0.9% 500ml over 30-60 minutes Intravenous infusion in 50ml sodium chloride 0.9% over 120 minutes Intravenous infusion in 500ml sodium chloride 0.9% starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour Cycle 2, 3, 4, 5, 6 Drug Bendamustine Rituximab Dose 90mg/m2 500mg/m2 Days 1, 2 1 Administration Intravenous infusion in sodium chloride 0.9% 500ml over 30-60 minutes Intravenous infusion in 500ml sodium chloride 0.9% as per your local rituximab administration guideline* Version 1.1 (July 2018) Page 4 of 10 CLL- Bendamustine (90)-Rituximab (Split) *If the lymphocyte is greater than 25x109/L on day one then consider fractionating the dose of rituximab as follows; Day 1 - rituximab 125mg/m2 in 100ml sodium chloride 0.9% Day 2 - rituximab 375mg/m2 in 500ml sodium chloride 0.9% If there were no problems with the previous infusion then start both fractions at 100mg/hour and escalate the rate in 100mg/hour increments every 30 minutes to a maximum rate of 400mg/hour. If reactions occurred with the previous cycle, give both fractions starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour Dose Information • Bendamustine will be dose banded according to the nationally agreed bands (2.5mg/ml) • A dose of rituximab from 325mg/m2 and above will be dose rounded to the nearest 100mg (up if halfway) Administration Information Extravasation • Bendamustine – vesicant • Rituximab - neutral Other • The rate of administration of rituximab varies. Please refer to the rituximab administration guidelines. Additional Therapy • Antiemetics 15-30 minutes prior to chemotherapy - metoclopramide 10mg oral or intravenous - ondansetron 8mg oral or intravenous As take home medication - metoclopramide 10mg three times a day when required for nausea oral - ondansetron 8mg twice a day for three days oral (on day two please ensure the patient has taken the ondansetron at home). • Rituximab pre-medication 30 minutes prior to rituximab - chlorphenamine 10mg intravenous Version 1.1 (July 2018) Page 5 of 10 CLL- Bendamustine (90)-Rituximab (Split) - hydrocortisone 100mg intravenous - paracetamol 1000mg oral • Rituximab infusion reactions - hydrocortisone 100mg intravenous when required for rituximab infusion related reactions - salbutamol 2.5mg nebule when required for rituximab related bronchospasm - consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to steroids. • Patients with CLL are at risk of tumour lysis syndrome (TLS). The British Society of Haematology guidelines are a useful reference source. Oral allopurinol is one option for prophylaxis. The course should be kept as short as possible to reduce the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with concomitant bendamustine and allopurinol use. Intravenous rasburicase can be considered in high risk individuals. • Mouthwashes according to local or national policy on the treatment of mucositis. • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. Additional Information • Bendamustine metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme. Therefore, the potential for interaction with CYP1A2 exists. Always check for drug interactions. Coding • Procurement – X71.5 • Delivery – X72.1cycle 1, X72.2 cycle 2 onwards & X72.4 References 1.Fischer K, Cramer P, Busch R et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group.J.Clin.Oncol. 2011 Sep 10;29(26):3559-66. Version 1.1 (July 2018) Page 6 of 10 CLL- Bendamustine (90)-Rituximab (Split) REGIMEN SUMMARY Bendamustine (90)-Rituximab (Split) Cycle 1 Day One 1. Warning – Check blood transfusion status Administration Instructions Patients treated with bendamustine carry a lifelong risk of transfusion associated graft versus host disease. Where blood products are required these patients must receive ONLY IRRADIATED BLOOD PRODUCTS for life. Ensure transfusion departments are notified and the patient has been issued with an alert card to carry with them at all times. 2. Chlorphenamine 10mg intravenous 3. Hydrocortisone 100mg intravenous 4. Paracetamol 1000mg oral 5. Rituximab 100mg intravenous infusion in 50ml sodium chloride 0.9% over 120 minutes 6. Metoclopramide 10mg oral or intravenous 7. Ondansetron 8mg oral or intravenous Bendamustine 90mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes 8. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 9. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Cycle 1 Day Two 10. Warning – Check supportive medication taken Administration Instructions Please ensure that the patient has taken metoclopramide 10mg oral and ondansetron 8mg oral on the morning of treatment. If not please administer metoclopramide 10mg oral or intravenous and ondansetron 8mg oral or intravenous 15-30 minutes prior to chemotherapy. 11. Chlorphenamine 10mg intravenous 12. Hydrocortisone 100mg intravenous 13. Paracetamol 1000mg oral 14. Rituximab 325mg/m2 intravenous infusion in 500ml sodium chloride 0.9% Administration Guidelines Start at a rate of 50mg/hour and, if tolerated, increase by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour. Version 1.1 (July 2018) Page 7 of 10 CLL- Bendamustine (90)-Rituximab (Split) 15. Bendamustine 90mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes 16. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 17. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Take home medicines (Day One) 18. Metoclopramide 10mg three times a day when required oral 19. Ondansetron 8mg twice a day for three days oral starting on the evening of day one of treatment 20. Allopurinol 300mg once a day for 7 days 21. Aciclovir 400mg twice a day for 28 days oral 22. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday for 28 days oral Administration Instructions This may be administered as 480mg twice a day on Monday, Wednesday and Friday according to local practice Cycle 2, 3, 4, 5, 6 Day One 23. Chlorphenamine 10mg intravenous 24. Hydrocortisone 100mg intravenous 25. Paracetamol 1000mg oral 26. Rituximab 500mg/m2 intravenous infusion in 500ml sodium chloride 0.9% Administration Instructions Administer as per your local administration guidelines If the lymphocyte is greater than 25x109/L on day one then consider fractionating the dose of rituximab as follows; Day 1 - rituximab 125mg/m2 in 100ml sodium chloride 0.9% Day 2 - rituximab 375mg/m2 in 500ml sodium chloride 0.9% If there were no problems with the previous infusion then start both fractions at 100mg/hour and escalate the rate in 100mg/hour increments every 30 minutes to a maximum rate of 400mg/hour. If reactions occurred with the previous cycle, give both fractions starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour 27. Metoclopramide 10mg oral or intravenous 28. Ondansetron 8mg oral or intravenous 29. Bendamustine 90mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes Version 1.1 (July 2018) Page 8 of 10 CLL- Bendamustine (90)-Rituximab (Split) 30. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 31. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Cycles 2, 3, 4, 5, 6 Day Two 32. Warning – Check supportive medication taken Administration Instructions Please ensure that the patient has taken metoclopramide 10mg oral and ondansetron 8mg oral on the morning of treatment. If not please administer metoclopramide 10mg oral or intravenous and ondansetron 8mg oral or intravenous 15-30 minutes prior to chemotherapy. 33. Bendamustine 90mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes Take home medicines (Day One) 34. Metoclopramide 10mg three times a day when required oral 35. Ondansetron 8mg twice a day for three days oral starting on the evening of day one of treatment 36. Aciclovir 400mg twice a day for 28 days oral 37. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday for 28 days oral Administration Instructions This may be administered as 480mg twice a day on Monday, Wednesday and Friday according to local practice Version 1.1 (July 2018) Page 9 of 10 CLL- Bendamustine (90)-Rituximab (Split) DOCUMENT CONTROL Version Date Amendment Written By Approved By 1.1 July 2018 1 February 2017 Dose banding changed to national dose bands None Donna Kimber Pharmacy Technician Dr Deborah Wright Pharmacist Dr Deborah Wright Pharmacist Dr Helen Dignum Consultant Haematologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. Version 1.1 (July 2018) Page 10 of 10 CLL- Bendamustine (90)-Rituximab (Split)
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/CLL/Bendamustine-90-RituximabSplit.pdf

Bendamustine_90_Rituximab

Description: Chemotherapy Protocol CHRONIC LYMPHOCYTIC LEUKAEMIA BENDAMUSTINE (90)-RITUXIMAB There are multiple versions of this protocol in use that vary depending on the indication. Please ensure you have the correct protocol for the relevant diagnosis. Regimen • CLL – Bendamustine (90)-Rituximab Indication • First line treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients for whom fludarabine combination chemotherapy is not appropriate • Second, third or fourth line treatment of B-CLL (unlicensed indication) Toxicity Drug Bendamustine Rituximab Adverse Effect Transfusion related GVHD, Gastro-intestinal disturbances, fatigue, insomnia, cardiac dysfunction, hypotension/hypertension, hypersensitivity reactions, hypokalaemia. Severe cytokine release syndrome, increased incidence of infective complications, progressive multifocal leukoencephalopathy Patients treated with bendamustine carry a lifelong risk of transfusion associated graft versus host disease (TA-GVHD). Where blood products are required these patients must receive only irradiated blood products for life. Local blood transfusion departments must be notified as soon as the decision to treat is made and the patient must be issued with an alert card to carry with them at all times. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Drugs • FBC, LFTs and U&Es prior to day one of treatment • Check hepatitis B status before starting rituximab • The presence of a viral upper respiratory tract infection prior to treatment may increase the risk of rituximab associated hepatotoxicity. Patients should be assessed for any cold or flu-like symptoms prior to treatment. Version 1.1 (July 2018) Page 1 of 10 CLL- Bendamustine (90)-Rituximab Dose Modifications The dose modifications listed are for haematological, liver and renal function and some drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. In principle all dose reductions due to adverse drug reactions should not be re-escalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Haematological Dose modifications for haematological toxicity in the table below are for general guidance only. Always refer to the responsible consultant as any dose reductions or delays will be dependent on clinical circumstances and treatment intent. Low counts can be a consequence of bone marrow infiltration as well as drug toxicity. Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL (80g/L). Irradiated blood products must be used. Neutrophils (x109/L) more than 1 100% Dose Modifications 0.5-1 less than 0.5 or febrile neutropenia Platelets (x109/L) Delay until recovery and then give 100% 1st occurrence - delay until recovery and give 75% of the original dose 2nd occurrence - delay until recovery and give 50% of the original dose Dose Modifications more than 100 100% 25-100 less than 25 or bleeding Delay until recovery and give 100% 1st occurrence - delay until recovery and give 75% of the original dose 2nd occurrence - delay until recovery and give 50% of the original dose Version 1.1 (July 2018) Page 2 of 10 CLL- Bendamustine (90)-Rituximab Hepatic Impairment The approach may be different where abnormal liver function tests are due to disease. Drug Bendamustine Bilirubin (µmol/L) less than 21 21-51 more than 51 Dose (% of original dose) 100% 70% no information Rituximab Renal Impairment Drug Bendamustine N/A No dose adjustment needed Creatinine Clearance (ml/min) more than 10 10 or less Dose (% of original dose) 100% no information Rituximab N/A No dose adjustment needed Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. Bendamustine Skin Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis have been reported in patients who received bendamustine and allopurinol simultaneously. If patients experience any skin reactions during treatment, they should be monitored closely and, in the case of any suspicion of the skin reaction evolving to a serious muco-cutaneous reaction, treatment with bendamustine should be withheld until complete resolution of the event or discontinued. Other potential causes of skin toxicity should be evaluated and suspected agents discontinued accordingly. Infusion Reactions Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials. Symptoms are generally mild and include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred. Patients must be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Measures to prevent severe reactions, including antihistamines, paracetamol and corticosteroids must be considered in Version 1.1 (July 2018) Page 3 of 10 CLL- Bendamustine (90)-Rituximab subsequent cycles in patients who have previously experienced infusion related reactions. Potassium In patients with cardiac dysfunction ensure the potassium remains above 3.5mmol/L during treatment with bendamustine. Rituximab Infusion Reactions Infusion related adverse reactions have been observed in 10% of patients treated with rituximab. The administration of rituximab in those with a diagnosis of CLL is more complex than for lymphomas. The risk of an infusion related reaction is much greater. To prevent this reaction, the cycle one dose is split over two days. In general the higher the white cell count, the greater is the risk of a reaction. Rituximab administration is associated with the onset of cytokine release syndrome. This condition is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. It may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, acute renal failure, elevated lactate dehydrogenase (LDH) and can lead to acute respiratory failure and death. This effect on the lungs may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. Cytokine release syndrome frequently occurs within two hours of initiating the first infusion. Hypersensitivity reactions, including anaphylaxis, have been reported following the intravenous administration of proteins. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes of starting the infusion. Medicinal products for the treatment of allergic reactions should be available for immediate use in the event of hypersensitivity developing during the administration of rituximab. Neurological Use of rituximab may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening neurological, cognitive or psychiatric symptoms that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed the rituximab must be permanently discontinued. Regimen 28 day cycle for 6 cycles Cycle 1 Version 1.1 (July 2018) Page 4 of 10 CLL- Bendamustine (90)-Rituximab Drug Bendamustine Rituximab Dose 90mg/m2 375mg/m2 Days 1, 2 1 Administration Intravenous infusion in sodium chloride 0.9% 500ml over 30-60 minutes Intravenous infusion in 500ml sodium chloride 0.9% starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour Cycle 2, 3, 4, 5, 6 Drug Dose Bendamustine 90mg/m2 Rituximab 500mg/m2 Days 1, 2 1 Administration Intravenous infusion in sodium chloride 0.9% 500ml over 30-60 minutes Intravenous infusion in 500ml sodium chloride 0.9% as per the rituximab administration guidelines Dose Information • Bendamustine will be dose banded according to the nationally agreed bands (2.5mg/ml) • Rituximab will be dose rounded to the nearest 100mg (up if halfway) Administration Information Extravasation • Bendamustine – vesicant • Rituximab - neutral Other • The rate of administration of rituximab varies. Please refer to the rituximab administration guidelines. Additional Therapy • Antiemetics 15-30 minutes prior to chemotherapy - metoclopramide 10mg oral or intravenous - ondansetron 8mg oral or intravenous As take home medication - metoclopramide 10mg three times a day when required for nausea oral - ondansetron 8mg twice a day for three days oral (on day two please ensure the patient has taken the ondansetron at home). • Rituximab pre-medication Version 1.1 (July 2018) Page 5 of 10 CLL- Bendamustine (90)-Rituximab 30 minutes prior to rituximab - chlorphenamine 10mg intravenous - hydrocortisone 100mg intravenous - paracetamol 1000mg oral • Rituximab infusion reactions - hydrocortisone 100mg intravenous when required for rituximab infusion related reactions - salbutamol 2.5mg nebule when required for rituximab related bronchospasm - consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to steroids. • Patients with CLL are at risk of tumour lysis syndrome (TLS). The British Society of Haematology guidelines are a useful reference source. Oral allopurinol is one option for prophylaxis. The course should be kept as short as possible to reduce the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with concomitant bendamustine and allopurinol use. Intravenous rasburicase can be considered in high risk individuals. • Mouthwashes according to local or national policy on the treatment of mucositis. • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. Additional Information • Bendamustine metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme. Therefore, the potential for interaction with CYP1A2 exists. Always check for drug interactions. Coding • Procurement – X71.5 • Delivery – X72.1cycle 1, X72.2 cycle 2 onwards & X72.4 References 1.Fischer K, Cramer P, Busch R et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group.J.Clin.Oncol. 2011 Sep 10;29(26):3559-66. Version 1.1 (July 2018) Page 6 of 10 CLL- Bendamustine (90)-Rituximab REGIMEN SUMMARY Bendamustine (90)-Rituximab Cycle 1 Day One 1. Warning – Check blood transfusion status Administration Instructions Patients treated with bendamustine carry a lifelong risk of transfusion associated graft versus host disease. Where blood products are required these patients must receive ONLY IRRADIATED BLOOD PRODUCTS for life. Ensure transfusion departments are notified and the patient has been issued with an alert card to carry with them at all times. 2. Chlorphenamine 10mg intravenous 3. Hydrocortisone 100mg intravenous 4. Paracetamol 1000mg oral 5. Rituximab 375mg/m2 intravenous infusion in 500ml sodium chloride 0.9% as per rituximab administration guidelines Administration Instructions The rate of administration of rituximab varies. Please refer to your local rituximab administration guidelines. 6. Metoclopramide 10mg oral or intravenous 7. Ondansetron 8mg oral or intravenous Bendamustine 90mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes 8. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 9. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Cycle 1 Day Two 10. Warning – Check supportive medication taken Administration Instructions Please ensure that the patient has taken metoclopramide 10mg oral and ondansetron 8mg oral on the morning of treatment. If not please administer metoclopramide 10mg oral or intravenous and ondansetron 8mg oral or intravenous 15-30 minutes prior to chemotherapy. 11. Bendamustine 90mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes Take home medicines (Day One) 12. Metoclopramide 10mg three times a day when required oral Version 1.1 (July 2018) Page 7 of 10 CLL- Bendamustine (90)-Rituximab 13. Ondansetron 8mg twice a day for three days oral starting on the evening of day one of treatment 14. Allopurinol 300mg once a day for 7 days 15. Aciclovir 400mg twice a day for 28 days oral 16. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday for 28 days oral Administration Instructions This may be administered as 480mg twice a day on Monday, Wednesday and Friday according to local practice Cycle 2, 3, 4, 5, 6 Day One 17. Chlorphenamine 10mg intravenous 18. Hydrocortisone 100mg intravenous 19. Paracetamol 1000mg oral 20. Rituximab 500mg/m2 intravenous infusion in 500ml sodium chloride 0.9% as per the rituximab administration guidelines Administration Instructions The rate of administration of rituximab varies. Please refer to your local rituximab administration guidelines. 21. Metoclopramide 10mg oral or intravenous 22. Ondansetron 8mg oral or intravenous 23. Bendamustine 90mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes 24. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 25. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Cycles 2, 3, 4, 5, 6 Day Two 26. Warning – Check supportive medication taken Administration Instructions Please ensure that the patient has taken metoclopramide 10mg oral and ondansetron 8mg oral on the morning of treatment. If not please administer metoclopramide 10mg oral or intravenous and ondansetron 8mg oral or intravenous 15-30 minutes prior to chemotherapy. 27. Bendamustine 90mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes Version 1.1 (July 2018) Page 8 of 10 CLL- Bendamustine (90)-Rituximab Take home medicines (Day One) 2. Metoclopramide 10mg three times a day when required oral 3. Ondansetron 8mg twice a day for three days oral starting on the evening of day one of treatment 4. Aciclovir 400mg twice a day for 28 days oral 5. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday for 28 days oral Administration Instructions This may be administered as 480mg twice a day on Monday, Wednesday and Friday according to local practice Version 1.1 (July 2018) Page 9 of 10 CLL- Bendamustine (90)-Rituximab DOCUMENT CONTROL Version Date Amendment Written By Approved By 1.1 July 2018 Dose bands changed to national dose bands Donna Kimber Pharmacy Technician 1 February 2017 None Dr Deborah Wright Pharmacist Dr Deborah Wright Pharmacist Dr Helen Dignum Consultant Haematologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. Version 1.1 (July 2018) Page 10 of 10 CLL- Bendamustine (90)-Rituximab
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/CLL/Bendamustine-90-Rituximab.pdf

Bendamustine_70_RituximabSplit

Description: Chemotherapy Protocol CHRONIC LYMPHOCYTIC LEUKAEMIA BENDAMUSTINE (70)-RITUXIMAB (Split) This protocol may require funding There are multiple versions of this protocol in use that vary depending on the indication. Please ensure you have the correct protocol for the relevant diagnosis. Regimen • CLL – Bendamustine (70)-Rituximab (Split) Indication • First line treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients for whom fludarabine combination chemotherapy is not appropriate • Second, third or fourth line treatment of B-CLL (unlicensed indication) • Split dose rituximab is indicated where the lymphocyte count is greater than 25x109/L Toxicity Drug Bendamustine Rituximab Adverse Effect Transfusion related GVHD, Gastro-intestinal disturbances, fatigue, insomnia, cardiac dysfunction, hypotension/hypertension, hypersensitivity reactions, hypokalaemia. Severe cytokine release syndrome, increased incidence of infective complications, progressive multifocal leukoencephalopathy Patients treated with bendamustine carry a lifelong risk of transfusion associated graft versus host disease (TA-GVHD). Where blood products are required these patients must receive only irradiated blood products for life. Local blood transfusion departments must be notified as soon as the decision to treat is made and the patient must be issued with an alert card to carry with them at all times. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Drugs • FBC, LFTs and U&Es prior to day one of treatment • Check hepatitis B status before starting rituximab • The presence of a viral upper respiratory tract infection prior to treatment may increase the risk of rituximab associated hepatotoxicity. Patients should be assessed for any cold or flu-like symptoms prior to treatment. Version 1.1 (July 2018) Page 1 of 10 CLL- Bendamustine (70)-Rituximab (Split) Dose Modifications The dose modifications listed are for haematological, liver and renal function and some drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. In principle all dose reductions due to adverse drug reactions should not be re-escalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Haematological Dose modifications for haematological toxicity in the table below are for general guidance only. Always refer to the responsible consultant as any dose reductions or delays will be dependent on clinical circumstances and treatment intent. Low counts can be a consequence of bone marrow infiltration as well as drug toxicity. Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL (80g/L). Irradiated blood products must be used. Neutrophils (x109/L) more than 1 100% Dose Modifications 0.5-1 less than 0.5 or febrile neutropenia Platelets (x109/L) Delay until recovery and then give 100% 1st occurrence - delay until recovery and give 75% of the original dose 2nd occurrence - delay until recovery and give 50% of the original dose Dose Modifications more than 100 100% 25-100 less than 25 or bleeding Delay until recovery and give 100% 1st occurrence - delay until recovery and give 75% of the original dose 2nd occurrence - delay until recovery and give 50% of the original dose Hepatic Impairment The approach may be different where abnormal liver function tests are due to disease. Drug Bendamustine Bilirubin (µmol/L) less than 21 21-51 more than 51 Dose (% of original dose) 100% 70% no information Rituximab N/A No dose adjustment needed Version 1.1 (July 2018) Page 2 of 10 CLL- Bendamustine (70)-Rituximab (Split) Renal Impairment Drug Bendamustine Creatinine Clearance (ml/min) more than 10 10 or less Dose (% of original dose) 100% no information Rituximab N/A No dose adjustment needed Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. Bendamustine Skin Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis have been reported in patients who received bendamustine and allopurinol simultaneously. If patients experience any skin reactions during treatment, they should be monitored closely and, in the case of any suspicion of the skin reaction evolving to a serious muco-cutaneous reaction, treatment with bendamustine should be withheld until complete resolution of the event or discontinued. Other potential causes of skin toxicity should be evaluated and suspected agents discontinued accordingly. Infusion Reactions Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials. Symptoms are generally mild and include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred. Patients must be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Measures to prevent severe reactions, including antihistamines, paracetamol and corticosteroids must be considered in subsequent cycles in patients who have previously experienced infusion related reactions. Potassium In patients with cardiac dysfunction ensure the potassium remains above 3.5mmol/L during treatment with bendamustine. Rituximab Infusion Reactions Infusion related adverse reactions have been observed in 10% of patients treated with rituximab. The administration of rituximab in those with a diagnosis of CLL is more complex than for lymphomas. The risk of an infusion related reaction is much greater. To prevent this reaction, the cycle one dose is split over two days. In general the higher the white cell count, the greater is the risk of a reaction. Version 1.1 (July 2018) Page 3 of 10 CLL- Bendamustine (70)-Rituximab (Split) Rituximab administration is associated with the onset of cytokine release syndrome. This condition is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. It may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, acute renal failure, elevated lactate dehydrogenase (LDH) and can lead to acute respiratory failure and death. This effect on the lungs may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. Cytokine release syndrome frequently occurs within one or two hours of initiating the first infusion. Hypersensitivity reactions, including anaphylaxis, have been reported following the intravenous administration of proteins. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes of starting the infusion. Medicinal products for the treatment of allergic reactions should be available for immediate use in the event of hypersensitivity developing during the administration of rituximab. Neurological Use of rituximab may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening neurological, cognitive or psychiatric symptoms that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed the rituximab must be permanently discontinued. Regimen 28 day cycle for 6 cycles Cycle 1 Drug Bendamustine Rituximab Rituximab Dose 70mg/m2 100mg 325mg/m2 Days 1, 2 1 2 Administration Intravenous infusion in sodium chloride 0.9% 500ml over 30-60 minutes Intravenous infusion in 50ml sodium chloride 0.9% over 120 minutes Intravenous infusion in 500ml sodium chloride 0.9% starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour Cycle 2, 3, 4, 5, 6 Drug Bendamustine Rituximab Dose 70mg/m2 500mg/m2 Days 1, 2 1 Administration Intravenous infusion in sodium chloride 0.9% 500ml over 30-60 minutes Intravenous infusion in 500ml sodium chloride 0.9% as per your local rituximab administration guidelines* *If the lymphocyte is greater than 25x109/L on day one then consider fractionating the dose of rituximab as follows; Version 1.1 (July 2018) Page 4 of 10 CLL- Bendamustine (70)-Rituximab (Split) Day 1 - rituximab 125mg/m2 in 100ml sodium chloride 0.9% Day 2 - rituximab 375mg/m2 in 500ml sodium chloride 0.9% If there were no problems with the previous infusion then start both fractions at 100mg/hour and escalate the rate in 100mg/hour increments every 30 minutes to a maximum rate of 400mg/hour. If reactions occurred with the previous cycle, give both fractions starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour. Dose Information • Bendamustine will be dose banded according to the nationally agreed bands (2.5mg/ml) • A dose of rituximab from 325mg/m2 and above will be dose rounded to the nearest 100mg (up if halfway) Administration Information Extravasation • Bendamustine – vesicant • Rituximab - neutral Other • The rate of administration of rituximab varies. Please refer to your local rituximab administration guidelines. Additional Therapy • Antiemetics 15-30 minutes prior to chemotherapy - metoclopramide 10mg oral or intravenous - ondansetron 8mg oral or intravenous As take home medication - metoclopramide 10mg three times a day when required for nausea oral - ondansetron 8mg twice a day for three days oral (on day two please ensure the patient has taken the ondansetron at home). • Rituximab pre-medication 30 minutes prior to rituximab - chlorphenamine 10mg intravenous - hydrocortisone 100mg intravenous - paracetamol 1000mg oral Version 1.1 (July 2018) Page 5 of 10 CLL- Bendamustine (70)-Rituximab (Split) • Rituximab infusion reactions - hydrocortisone 100mg intravenous when required for rituximab infusion related reactions - salbutamol 2.5mg nebule when required for rituximab related bronchospasm - consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to steroids. • Patients with CLL are at risk of tumour lysis syndrome (TLS). The British Society of Haematology guidelines are a useful reference source. Oral allopurinol is one option for prophylaxis. The course should be kept as short as possible to reduce the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with concomitant bendamustine and allopurinol use. Intravenous rasburicase can be considered in high risk individuals. • Mouthwashes according to local or national policy on the treatment of mucositis. • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. Additional Information • Bendamustine metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme. Therefore, the potential for interaction with CYP1A2 exists. Always check for drug interactions. Coding • Procurement – X71.5 • Delivery – X72.1cycle 1, X72.2 cycle 2 onwards & X72.4 References 1.Fischer K, Cramer P, Busch R et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group.J.Clin.Oncol. 2011 Sep 10;29(26):3559-66. Version 1.1 (July 2018) Page 6 of 10 CLL- Bendamustine (70)-Rituximab (Split) REGIMEN SUMMARY Bendamustine (70)-Rituximab (Split) Cycle 1 Day One 1. Warning – Check blood transfusion status Administration Instructions Patients treated with bendamustine carry a lifelong risk of transfusion associated graft versus host disease. Where blood products are required these patients must receive ONLY IRRADIATED BLOOD PRODUCTS for life. Ensure transfusion departments are notified and the patient has been issued with an alert card to carry with them at all times. 2. Chlorphenamine 10mg intravenous 3. Hydrocortisone 100mg intravenous 4. Paracetamol 1000mg oral 5. Rituximab 100mg intravenous infusion in 50ml sodium chloride 0.9% over 120 minutes 6. Metoclopramide 10mg oral or intravenous 7. Ondansetron 8mg oral or intravenous 8. Bendamustine 70mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes 9. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 10. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Cycle 1 Day Two 11. Warning – Check supportive medication taken Administration Instructions Please ensure that the patient has taken metoclopramide 10mg oral and ondansetron 8mg oral on the morning of treatment. If not please administer metoclopramide 10mg oral or intravenous and ondansetron 8mg oral or intravenous 15-30 minutes prior to chemotherapy. 12. Chlorphenamine 10mg intravenous 13. Hydrocortisone 100mg intravenous 14. Paracetamol 1000mg oral 15. Rituximab 325mg/m2 intravenous infusion in 500ml sodium chloride 0.9% Administration Guidelines Start at a rate of 50mg/hour and, if tolerated, increase by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour. Version 1.1 (July 2018) Page 7 of 10 CLL- Bendamustine (70)-Rituximab (Split) 16. Bendamustine 70mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes 17. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 18. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Take home medicines (Day One) 19. Metoclopramide 10mg three times a day when required oral 20. Ondansetron 8mg twice a day for three days oral starting on the evening of day one of treatment 21. Allopurinol 300mg once a day for 7 days 22. Aciclovir 400mg twice a day for 28 days oral 23. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday for 28 days oral Administration Instructions This may be administered as 480mg twice a day on Monday, Wednesday and Friday according to local practice Cycle 2, 3, 4, 5, 6 Day One 24. Chlorphenamine 10mg intravenous 25. Hydrocortisone 100mg intravenous 26. Paracetamol 1000mg oral 27. Rituximab 500mg/m2 intravenous infusion in 500ml sodium chloride 0.9% Administration Instructions Administer as per your local administration guidelines. If the lymphocyte is greater than 25x109/L on day one then consider fractionating the dose of rituximab as follows; Day 1 - rituximab 125mg/m2 in 100ml sodium chloride 0.9% Day 2 - rituximab 375mg/m2 in 500ml sodium chloride 0.9% If there were no problems with the previous infusion then start both fractions at 100mg/hour and escalate the rate in 100mg/hour increments every 30 minutes to a maximum rate of 400mg/hour. If reactions occurred with the previous cycle, give both fractions starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour 28. Metoclopramide 10mg oral or intravenous 29. Ondansetron 8mg oral or intravenous 30. Bendamustine 70mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes Version 1.1 (July 2018) Page 8 of 10 CLL- Bendamustine (70)-Rituximab (Split) 31. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 32. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Cycles 2, 3, 4, 5, 6 Day Two 33. Warning – Check supportive medication taken Administration Instructions Please ensure that the patient has taken metoclopramide 10mg oral and ondansetron 8mg oral on the morning of treatment. If not please administer metoclopramide 10mg oral or intravenous and ondansetron 8mg oral or intravenous 15-30 minutes prior to chemotherapy. 34. Bendamustine 70mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes Take home medicines (Day One) 2. Metoclopramide 10mg three times a day when required oral 3. Ondansetron 8mg twice a day for three days oral starting on the evening of day one of treatment 4. Aciclovir 400mg twice a day for 28 days oral 5. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday for 28 days oral Administration Instructions This may be administered as 480mg twice a day on Monday, Wednesday and Friday according to local practice Version 1.1 (July 2018) Page 9 of 10 CLL- Bendamustine (70)-Rituximab (Split) DOCUMENT CONTROL Version Date Amendment Written By Approved By 1.1 July 2018 Bendamustine dose bands changed to national dose bands Donna Kimber Pharmacy Technician 1 February 2017 None Dr Deborah Wright Pharmacist Dr Deborah Wright Pharmacist Dr Helen Dignum Consultant Haematologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. Version 1.1 (July 2018) 10 Page 10 of CLL- Bendamustine (70)-Rituximab (Split)
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/CLL/Bendamustine-70-RituximabSplit.pdf

Bendamustine_70_Rituximab

Description: Chemotherapy Protocol CHRONIC LYMPHOCYTIC LEUKAEMIA BENDAMUSTINE (70)-RITUXIMAB There are multiple versions of this protocol in use that vary depending on the indication. Please ensure you have the correct protocol for the relevant diagnosis. Regimen • CLL – Bendamustine (70)-Rituximab Indication • First line treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients for whom fludarabine combination chemotherapy is not appropriate • Second, third or fourth line treatment of B-CLL (unlicensed indication) Toxicity Drug Bendamustine Rituximab Adverse Effect Transfusion related GVHD, Gastro-intestinal disturbances, fatigue, insomnia, cardiac dysfunction, hypotension/hypertension, hypersensitivity reactions, hypokalaemia. Severe cytokine release syndrome, increased incidence of infective complications, progressive multifocal leukoencephalopathy Patients treated with bendamustine carry a lifelong risk of transfusion associated graft versus host disease (TA-GVHD). Where blood products are required these patients must receive only irradiated blood products for life. Local blood transfusion departments must be notified as soon as the decision to treat is made and the patient must be issued with an alert card to carry with them at all times. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Drugs • FBC, LFTs and U&Es prior to day one of treatment • Check hepatitis B status before starting rituximab • The presence of a viral upper respiratory tract infection prior to treatment may increase the risk of rituximab associated hepatotoxicity. Patients should be assessed for any cold or flu-like symptoms prior to treatment. Version 1.1 (July 2018) Page 1 of 10 CLL- Bendamustine (70)-Rituximab Dose Modifications The dose modifications listed are for haematological, liver and renal function and some drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. In principle all dose reductions due to adverse drug reactions should not be re-escalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Haematological Dose modifications for haematological toxicity in the table below are for general guidance only. Always refer to the responsible consultant as any dose reductions or delays will be dependent on clinical circumstances and treatment intent. Low counts can be a consequence of bone marrow infiltration as well as drug toxicity. Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL (80g/L). Irradiated blood products must be used. Neutrophils (x109/L) more than 1 100% Dose Modifications 0.5-1 less than 0.5 or febrile neutropenia Platelets (x109/L) Delay until recovery and then give 100% 1st occurrence - delay until recovery and give 75% of the original dose 2nd occurrence - delay until recovery and give 50% of the original dose Dose Modifications more than 100 100% 25-100 less than 25 or bleeding Delay until recovery and give 100% 1st occurrence - delay until recovery and give 75% of the original dose 2nd occurrence - delay until recovery and give 50% of the original dose Hepatic Impairment The approach may be different where abnormal liver function tests are due to disease. Version 1.1 (July 2018) Page 2 of 10 CLL- Bendamustine (70)-Rituximab Drug Bendamustine Bilirubin (µmol/L) less than 21 21-51 more than 51 Dose (% of original dose) 100% 70% no information Rituximab Renal Impairment Drug Bendamustine N/A No dose adjustment needed Creatinine Clearance (ml/min) more than 10 10 or less Dose (% of original dose) 100% no information Rituximab N/A No dose adjustment needed Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. Bendamustine Skin Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis have been reported in patients who received bendamustine and allopurinol simultaneously. If patients experience any skin reactions during treatment, they should be monitored closely and, in the case of any suspicion of the skin reaction evolving to a serious muco-cutaneous reaction, treatment with bendamustine should be withheld until complete resolution of the event or discontinued. Other potential causes of skin toxicity should be evaluated and suspected agents discontinued accordingly. Infusion Reactions Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials. Symptoms are generally mild and include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred. Patients must be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Measures to prevent severe reactions, including antihistamines, paracetamol and corticosteroids must be considered in subsequent cycles in patients who have previously experienced infusion related reactions. Version 1.1 (July 2018) Page 3 of 10 CLL- Bendamustine (70)-Rituximab Potassium In patients with cardiac dysfunction ensure the potassium remains above 3.5mmol/L during treatment with bendamustine. Rituximab Infusion Reactions Infusion related adverse reactions have been observed in 10% of patients treated with rituximab. The administration of rituximab in those with a diagnosis of CLL is more complex than for lymphomas. The risk of an infusion related reaction is much greater. To prevent this reaction, the cycle one dose is split over two days. In general the higher the white cell count, the greater is the risk of a reaction. Rituximab administration is associated with the onset of cytokine release syndrome. This condition is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. It may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, acute renal failure, elevated lactate dehydrogenase (LDH) and can lead to acute respiratory failure and death. This effect on the lungs may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. Cytokine release syndrome frequently occurs within two hours of initiating the first infusion. Hypersensitivity reactions, including anaphylaxis, have been reported following the intravenous administration of proteins. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes of starting the infusion. Medicinal products for the treatment of allergic reactions should be available for immediate use in the event of hypersensitivity developing during the administration of rituximab. Neurological Use of rituximab may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening neurological, cognitive or psychiatric symptoms that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed the rituximab must be permanently discontinued. Regimen 28 day cycle for 6 cycles Cycle 1 Drug Bendamustine Rituximab Dose 70mg/m2 375mg/m2 Day Administration s 1, 2 Intravenous infusion in sodium chloride 0.9% 500ml over 30-60 minutes Intravenous infusion in 500ml sodium chloride 0.9% 1 starting at a rate of 50mg/hour and, if tolerated, increasing by 50mg/hour every 30 minutes to a maximum rate of 400mg/hour Version 1.1 (July 2018) Page 4 of 10 CLL- Bendamustine (70)-Rituximab Cycle 2, 3, 4, 5, 6 Drug Dose Bendamustine 70mg/m2 Rituximab 500mg/m2 Days 1, 2 1 Administration Intravenous infusion in sodium chloride 0.9% 500ml over 30-60 minutes Intravenous infusion in 500ml sodium chloride 0.9% as per the rituximab administration guidelines Dose Information • Bendamustine will be dose banded according to the nationally agreed bands (2.5mg/ml) • Rituximab will be dose rounded to the nearest 100mg (up if halfway) Administration Information Extravasation • Bendamustine – vesicant • Rituximab - neutral Other • The rate of administration of rituximab varies. Please refer to the rituximab administration guidelines. Additional Therapy • Antiemetics 15-30 minutes prior to chemotherapy - metoclopramide 10mg oral or intravenous - ondansetron 8mg oral or intravenous As take home medication - metoclopramide 10mg three times a day when required for nausea oral - ondansetron 8mg twice a day for three days oral (on day two please ensure the patient has taken the ondansetron at home). • Rituximab pre-medication 30 minutes prior to rituximab - chlorphenamine 10mg intravenous - hydrocortisone 100mg intravenous - paracetamol 1000mg oral • Rituximab infusion reactions Version 1.1 (July 2018) Page 5 of 10 CLL- Bendamustine (70)-Rituximab - hydrocortisone 100mg intravenous when required for rituximab infusion related reactions - salbutamol 2.5mg nebule when required for rituximab related bronchospasm - consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to steroids. • Patients with CLL are at risk of tumour lysis syndrome (TLS). The British Society of Haematology guidelines are a useful reference source. Oral allopurinol is one option for prophylaxis. The course should be kept as short as possible to reduce the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with concomitant bendamustine and allopurinol use. Intravenous rasburicase can be considered in high risk individuals. • Mouthwashes according to local or national policy on the treatment of mucositis. • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. Additional Information • Bendamustine metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme. Therefore, the potential for interaction with CYP1A2 exists. Always check for drug interactions. Coding • Procurement – X71.5 • Delivery – X72.1cycle 1, X72.2 cycle 2 onwards & X72.4 References 1.Fischer K, Cramer P, Busch R et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group.J.Clin.Oncol. 2011 Sep 10;29(26):3559-66. Version 1.1 (July 2018) Page 6 of 10 CLL- Bendamustine (70)-Rituximab REGIMEN SUMMARY Bendamustine (70)-Rituximab Cycle 1 Day One 1. Warning – Check blood transfusion status Administration Instructions Patients treated with bendamustine carry a lifelong risk of transfusion associated graft versus host disease. Where blood products are required these patients must receive ONLY IRRADIATED BLOOD PRODUCTS for life. Ensure transfusion departments are notified and the patient has been issued with an alert card to carry with them at all times. 2. Chlorphenamine 10mg intravenous 3. Hydrocortisone 100mg intravenous 4. Paracetamol 1000mg oral 5. Rituximab 375mg/m2 intravenous infusion in 500ml sodium chloride 0.9% as per rituximab administration guidelines Administration Instructions The rate of administration of rituximab varies. Please refer to your local rituximab administration guidelines. 6. Metoclopramide 10mg oral or intravenous 7. Ondansetron 8mg oral or intravenous 8. Bendamustine 70mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes 9. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 10. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Cycle 1 Day Two 11. Warning – Check supportive medication taken Administration Instructions Please ensure that the patient has taken metoclopramide 10mg oral and ondansetron 8mg oral on the morning of treatment. If not please administer metoclopramide 10mg oral or intravenous and ondansetron 8mg oral or intravenous 15-30 minutes prior to chemotherapy. 12. Bendamustine 70mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes Take home medicines (Day One) 13. Metoclopramide 10mg three times a day when required oral Version 1.1 (July 2018) Page 7 of 10 CLL- Bendamustine (70)-Rituximab 14. Ondansetron 8mg twice a day for three days oral starting on the evening of day one of treatment 15. Allopurinol 300mg once a day for 7 days 16. Aciclovir 400mg twice a day for 28 days oral 17. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday for 28 days oral Administration Instructions This may be administered as 480mg twice a day on Monday, Wednesday and Friday according to local practice Cycle 2, 3, 4, 5, 6 Day One 18. Chlorphenamine 10mg intravenous 19. Hydrocortisone 100mg intravenous 20. Paracetamol 1000mg oral 21. Rituximab 500mg/m2 intravenous infusion in 500ml sodium chloride 0.9% as per the rituximab administration guidelines Administration Instructions The rate of administration of rituximab varies. Please refer to your local rituximab administration guidelines. 22. Metoclopramide 10mg oral or intravenous 23. Ondansetron 8mg oral or intravenous 24. Bendamustine 70mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes 25. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 26. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Cycles 2, 3, 4, 5, 6 Day Two 27. Warning – Check supportive medication taken Administration Instructions Please ensure that the patient has taken metoclopramide 10mg oral and ondansetron 8mg oral on the morning of treatment. If not please administer metoclopramide 10mg oral or intravenous and ondansetron 8mg oral or intravenous 15-30 minutes prior to chemotherapy. 28. Bendamustine 70mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes Version 1.1 (July 2018) Page 8 of 10 CLL- Bendamustine (70)-Rituximab Take home medicines (Day One) 29. Metoclopramide 10mg three times a day when required oral 30. Ondansetron 8mg twice a day for three days oral starting on the evening of day one of treatment 31. Aciclovir 400mg twice a day for 28 days oral 32. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday for 28 days oral Administration Instructions This may be administered as 480mg twice a day on Monday, Wednesday and Friday according to local practice Version 1.1 (July 2018) Page 9 of 10 CLL- Bendamustine (70)-Rituximab DOCUMENT CONTROL Version Date Amendment Written By Approved By 1.1 July 2018 1 February 2017 Dose banding changed to national dose bnds None Donna Kimber Pharmacy Technician Dr Deborah Wright Pharmacist Dr Deborah Wright Pharmacist Dr Helen Dignum Consultant Haematologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. Version 1.1 (July 2018) Page 10 of 10 CLL- Bendamustine (70)-Rituximab
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/CLL/Bendamustine-70-Rituximab.pdf

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